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Enantiodivergent Synthesis of Bis-Spiropyrrolidines via Sequential Interrupted and Completed (3 + 2) Cycloadditions Egoitz Conde, Ivan Rivilla, Amaia Larumbe, and Fernando P. Cossío J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01418 • Publication Date (Web): 06 Oct 2015 Downloaded from http://pubs.acs.org on October 7, 2015

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The Journal of Organic Chemistry

Enantiodivergent Synthesis of Bis-Spiropyrrolidines via Sequential Interrupted and Completed (3 + 2) Cycloadditions Egoitz Conde,1†,2‡ Iván Rivilla,‡ Amaia Larumbe, and Fernando P. Cossío* Department of Organic Chemistry I, Universidad del País Vasco / Euskal Herriko Unibertsitatea (UPV/EHU), Centro de Innovación en Química Avanzada (ORFEO-CINQA), and Donostia International Physics Center (DIPC), Pº Manuel Lardizabal 3, 20018 San Sebastián / Donostia, Spain

ABSTRACT: Both (5R) and (5S)-1,7-diazaspiro[4,4]nonan-6-ones are obtained via a sequence of interrupted and completed stepwise (3 + 2) cycloadditions between azomethine ylides and π−deficient alkenes. The only source of chirality along the whole process is an enantiopure ferrocenyl pyrrolidine catalytic ligand. When the starting imine incorporates two aryl groups or one aryl group with one electron-releasing substituent the reaction between the azomethine ylide and the alkene stops at the first step leading to the corresponding Michael adduct. When imines derived from p-methoxybenzaldehyde are used the corresponding syn−α−amino−γ−nitro ester is obtained with almost complete enantiocontrol. In contrast, imines derived from benzophenone lead to the corresponding anti analogue. From this interrupted (3 + 2) cycloaddition cis- and trans−α−amino−γ−lactams can be obtained via hydrogenation of the nitro group followed by in situ cyclization. Imines derived from these latter compounds are the precursors of N-metallated azomethine ylides, from which up to four new chiral centers can be generated via completed (3 + 2) cycloaddition reactions with full regio- and diastereocontrol. Cis and

1†

Present address: Université de Pau et des Pays de l’Adour, CNRS, IPREM, UMR 5254, F-64053 Pau, France.

2‡

These authors contributed equally to this work. 1 ACS Paragon Plus Environment


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trans−γ−lactams lead to opposite bis-spiropyrrolidine enantiomers. Therefore, both enantiomeric series of spiro compounds can be obtained by means of the same catalytic system. The potential of these rigid, densely substituted homochiral compounds in medicinal chemistry is briefly described. 1. Introduction Thermal cycloadditions can occur via concerted or stepwise mechanisms.1 In the case of (3 + 2) cycloadditions between N-metalated azomethine ylides INT1 (formed in situ from the corresponding imines 1) and nitroalkenes 2, the reaction usually occurs via zwitterionic intermediates INT22 (Scheme 1) that can evolve towards the corresponding pyrrolidine rings 3 thus completing the formal (3+2) cycloaddition. The reaction mechanism of the whole stepwise process consists of a conjugate addition of in situ formed azomethine ylide INT1 to Michael acceptor 2, followed by an intramolecular HenryMannich like cyclization. When INT2 species are stable enough, it is possible to frustrate the (3+2) cycloaddition and to isolate the corresponding α−amino−γ−nitroesters 4 after appropriate hydrolytic workup (Scheme 1).3 It is remarkable, however, that the synthetic potential provided by this stepwise mechanism has not been fully exploited for the asymmetric synthesis of polycyclic molecules, probably because of the difficulties associated with the control of completed and interrupted cycloadditions. Scheme 1. Synthesis of Pyrrolidines 3 and α−Amino−γ− −γ−nitro-esters 4 via Interrupted and Comα− −γ− pleted (3+2) Cycloadditions between Imines 1 and Nitroalkenes 2.

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The Journal of Organic Chemistry R4

O 2N

* R2 * *N * CO 2R 3 1 R

H 3

R2 R1

N

CO 2R 3

1

completed (3+2) cycloaddition

MX, Base R2 R1

N LnM

OR3 O

O O 2N

R4 2

work-up

N

O

*R *

R2 R1

N L nM

INT1

4

OR3

O

INT2 interrupted (3+2) cycloaddition

hydrolytic work-up

NO 2 4

H 2N

*R * CO R 3 2

4

Spiro compounds obtained via formal or effective (3+2)4 and (4+1)5 cycloadditions are of great relevance in medicinal chemistry. Among the different systems obtained so far the 1,7diazaspiro[4,4]nonane scaffold 56 has received little attention,7 possibly because of the accumulation of chiral centers and functional groups in the bicyclic system, which poses a considerable synthetic challenge. We reasoned that bicyclic compounds 5 could be readily obtained by means of completed (3 + 2) cycloadditions between azomethine ylides of type INT3 and π−deficient alkenes 2 or 7 (Scheme 2). In this cycloaddition, the whole stereocontrol relies only on one stereogenic center (Scheme 2). Azomethine ylides INT3 can in turn be readily accessible from aldehydes 8 and γ−lactams 6, which can be synthetized from the corresponding γ−nitro amino esters 4. These latter adducts should be obtained by a conjugate addition that corresponds to the first step of an interrupted (3 + 2) reaction between Nmetalated azomethine ylides INT1 and nitroalkenes 2. In this reaction, two issues must be addressed: (i) the stereocontrol in the generation of the two new chiral centers and (ii) the efficient interruption of the cyclization process to isolate the corresponding Michael adduct. 3 ACS Paragon Plus Environment


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Scheme 2. Synthesis of 1,7-Diazaspiro[4.4]nonan-6-ones 5 via Sequential Interrupted and Completed (3 + 2) Cycloadditions . R6 R5 HN N H 1,7-diazaspiro[4.4]nonane scaffold

7 * * * R 4 * R HN *

O

N H 5

completed (3+2) cycloaddition R2

R6

8 R5

O + R4 * O

R7

+

H 2N *

R4 *

N X O

N H 6

2, 7

N H INT3 NO 2 2

interrupted (3+2) cycloaddition

NO 2

R2 +

R4 * H 2N

*

R1 CO 2R 3

4

R4

N L nM O INT1

OR 3

Based on our previous studies in stereocontrolled stepwise (3 + 2) cycloadditions, we speculated that in the presence of a suitable catalyst of type EhuPhos previously described by our group and under carefully tuned reaction conditions, the reaction between azomethine ylides INT1 and nitroalkenes 2 could be stopped at the conjugate addition step, thus yielding intermediates 4 as a result of this frustrated (3 + 2) cycloaddition (Scheme 2). In this case, the stereochemistry of the two new chiral centers should be determined by the NH-D-EhuPhos catalytic ligand 9 (Table 1). Once this first goal is successfully addressed, the subsequent completed (3+2) cycloaddition should take place with complete stereocontrol induced by the R4 substituent.


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In this Article we present our results on the synthesis of homochiral bis-spiropyrrolodines by addressing the challenges posed by the required regio-, diastereo- and enantiocontrol as well as the adequate interruption or completion of the (3+2) processes involved. Finally, to illustrate the potential of these conformationally restricted compounds, we report several preliminary results on their biological activity associated with relevant targets in medicinal chemistry. 2. Results and Discussion 2.1. Interrupted (3+2) cycloadditions. Previous work carried out in our laboratory8 and in collaboration with Martin et al.9 showed that ferrocenyl compound 9 (NH-D-EhuPhos) is a very convenient catalytic ligand for (3 + 2) cycloadditions. With these results in mind, we tried to stop the reaction between imine 1a and nitroalkene 2a in the presence of ligand 9. The results obtained are gathered in Table 1. Our experiments showed that at -20 ºC the (3 + 2) cycloaddition was completed and 4a could not be observed. Instead, cycloadduct exo-3a was obtained (with a small amount of endo-3a in a exo:endo ratio of 95:05) in nice agreement with our previously reported results8a (Table 1, entry 1). When the temperature was lowered to -80 ºC the amount of Michael adduct syn-4a grow to achieve a exo-3a:syn-4a ratio of 30:70, giving Michael adduct syn-4a in 53 % yield and with an ee of 96 % (Table 1, entry 3). Unfortunately, the exo-3a:syn-4a ratio could not be improved by lowering the reaction temperature at -95 ºC for 60 h (Table 1, entry 4), thus showing that the results corresponding to entry 3 are the best ones that can be achieved with imine 1a (R=Ph). Lower stereocontrol was observed when AgOAc was used as an alternative metallic source. Similarly, other bases (DBU, t-BuOK, Cs2CO3) and solvents (1,4-dioxane, toluene) resulted in lower stereocontrol and/or chemical yields.

Table 1. Interrupted and Completed (3 + 2) Cycloadditions between Imines 1a,b and Nitroalkene 2a



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Ph CO 2Me

i: O2N

Ph

N H

Fe

N 1a,b

N H

Cu(CH 3CN) 4PF 6 (Y mol %) CO 2Me THF, NEt 3 (5.0 mol %) ii: HCl 1N (2.0 eq.) iii: NaHCO 3, H 2O, pH 8.0

CO 2Me

exo-3a,b + NO 2 Ph

9 (X mol %)

a: R=Ph b: R=PMP

a

R

PPh 2

2a + R

Ph

O 2N

O2N

H 2N CO 2Me syn-4a

Entry

R

T (ºC)

X,Y (mol %)

Time (h)

exo-3: syn-4aa

yield (%)b

ee (%)c

1

Ph

-20

3.3, 3.0

15

>99:01

85

97

2

Ph

-40

3.3, 3.0

15

69:31

n.d.d

n.d. d

3

Ph

-80

3.3, 3.0

5

30:70

53

96

4

Ph

-95

3.3, 3.0

60

30:70

n.d. d

n.d. d

5

PMP

-40

3.3, 3.0

0.5

99

6

PMP

-60

1.1, 1.0

0.5

99

7

PMP

-60

0.6, 0.5

0.5

99

2

1b

2b

4b

Me

4-F-C6H4

85

>99

3

1b

2c

4c

Me

4-MeO-C6H4

85

>99

4

1b

2d

4d

Me

4-Me-C6H4

86

>99

5

1b

2e

4e

Me

2-F- C6H4

80

>99

6

1b

2f

4f

Me

2-Furyl

75

95

7

1c

2a

4g

Et

Ph

85

>99

8

1d

2a

4h

t-Bu

Ph

58

>99

In all cases the measured syn-4:anti-4 ratio was >99:01. bIsolated yield of the major adduct. cDeter-

mined by HPLC (see the Supporting Information). In order to evaluate the stepwise nature of these reactions and the role of Michael intermediates as precursors of (3 + 2) cycloadditions, we monitored by NMR the evolution of the reaction between imine 1b and nitroalkene 2a at different temperatures (Scheme 3). According to our results, after 12 h of reaction at -60 ºC only imine 4’b (precursor of 4a) was detected by 1H- and

13

C-NMR (COSY and

DEPT experiments, see the Supporting Information). When the temperature of the reaction mixture was allowed to reach room temperature, a 80:20 mixture of exo-3b and endo-3b was obtained. This result demonstrates not only the evolution of 4’b towards the iminium-nitronate intermediate INT2 and the 8 ACS Paragon Plus Environment

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corresponding (3 + 2) cycloadducts 3b, but also the reversibility of the Michael addition step, since a noticeable amount of endo-3b was observed. Interestingly, when the reaction between 1b and 2a was carried out at room temperature, a 50:50 mixture of both diastereomers 4b was observed, thus confirming the importance of the temperature to stop the stepwise reaction at its first step, as well as to keep the stereoselectivity of the initial Michael addition under control. Scheme 3. Evolution of Michael Intermediates Obtained from Imine 1b towards (3 + 2) Cycloadducts.a

a

Reagents: (i) 9 (1.0 mol %), THF, NEt3 (5.0 mol %), Cu(CH3CN)4PF6 (1.0 mol %). On the basis of the above results, we reasoned that an alternative way to stabilize the iminium

moiety of zwitterionic intermediates INT2 could consist of incorporating an additional phenyl group to the starting imines. Therefore, we studied the possibly of interrupting (3 + 2) cycloadditions between imines 1e-g and nitroalkenes 2a-f. The results of these experiments are collected in Table 3. Also in this case, under the previously optimized reaction conditions we observed only the formation of α−amino−γ−nitro esters 4a-h, but in this case the anti diastereomers were obtained as major or exclusive (Table 3, entry 6) adducts. In general both the enantiocontrol and the chemical yields were excellent, with the exception of adducts 4d and 4h (Table 3, entries 4 and 8), for which the isolated yields were somewhat lower but still acceptable. 9 ACS Paragon Plus Environment


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Table 3. Interrupted (3+2) Cycloadditions between Imines 1e-g and Nitroalkenes 2a-f to Yield (2S,3R)−α− −α−Amino−γ− −γ−nitro Esters anti-4a-h. −α− −γ−

O 2N

i: 9 (1.0 mol %), -60 ºC Cu(CH3CN) 4PF 6 (1.0 mol %) THF, NEt 3 (5.0 mol %)

R2

2a-f Ph + Ph

CO 2R1

N

ii: HCl 1N (2.0 eq.) iii: NaHCO 3, H 2O, pH 8.0

R2 H 2N

CO 2R1

anti-4a-h

1e-g

a

NO 2

Entry 1

2

4a

R1

R2

Yieldb (%)

eec (%)

1

1e

2a

4a

Me

Ph

89

95

2

1e

2b

4b

Me

4-F-C6H4

82

90

3

1e

2c

4c

Me

4-MeO-C6H4

84

90

4

1e

2d

4d

Me

4-Me-C6H4

71

94

5

1e

2e

4e

Me

2-F- C6H4

94

93

6

1e

2f

4f

Me

2-Furyl

81

96

7

1f

2a

4g

Et

Ph

83

93

8

1g

2a

4h

t-Bu

Ph

68

97

In all cases the measured anti-4:syn-4 ratio was >99:01, except in entry 6, for which the ratio was

94:06. bIsolated yield of the major adduct. cDetermined by HPLC (see the Supporting Information).


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NMR experiments similar to those carried out for the reaction between imine 1b and nitroalkene 2a showed a more reluctant evolution of the Michael intermediates towards the corresponding cycloadducts. Thus, no cycloadduct 3e was observed when the reaction was conducted at room temperature (Scheme 4), anti-4’e being the only reaction product observed by NMR after 12 h of reaction (see the Supporting Information). Under refluxing THF complete conversion of anti-4’e into endo-3e was observed after 12 h. Microwave irradiation for 3 h was more efficient in this respect and promoted complete conversion of 1e and 2a into endo-3e. However, under both classical and dielectric heating this latter cycloadduct was obtained as a racemic mixture. Scheme 4. Evolution of Michael Intermediate Obtained from Imine 1e towards (3 + 2) Cycloadduct 3e.a

a

Reagents: (i) 9 (1.0 mol %), THF, NEt3 (5.0 mol %), Cu(CH3CN)4PF6 (1.0 mol %). From these data, we propose that the whole reaction mechanism involves two catalytic cycles

(Scheme 5). Chiral ligand 9 and Cu(I) salt form complex INT0 with imines 1 (immediate formation of this complex was observed by 31P-NMR, results not shown). Reaction with the amine results in the formation of azomethine ylide INT1, which can add one equivalent of dipolarophile (or Michael acceptor) 2 to form zwitterionic intermediate INT2 (Scheme 5, step a). This latter intermediate can be reprotonat11 ACS Paragon Plus Environment


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ed by the conjugate acid of the tertiary amine to form INT4, which in turn generates Michael adduct 4’ (observed by NMR in untreated reaction mixtures) and releases the catalyst-imine complex. At higher temperatures, reversible steps c, b, and even a can proceed towards the product of thermodynamic control. Therefore, INT2 instead of being reprotonated (step b) can form another C-C bond by an intramolecular Mannich-Henry reaction between the nitronate and iminium moieties (step d), thus completing the catalytic cycle associated with (3 + 2) cycloaddition and yielding pyrrolidine 3. Scheme 5. Mechanistic Proposal for the Interrupted and Completed (3 + 2) Reaction between Nitroalkenes and Imines under Catalytic Conditions NO2

NO2 H3

R''

O+

OMe

H 2N

R'

R''

R' R

R

OMe

N

O

N

CO2Me

1

O 4'

4

9 interrupted cycloaddition

R'

c R NO2

R 9 PF6-

N Cu

N Cu O 9 PF6INT0

1 low temperature

R''

R'

+ Cu(CH3CN)4PF6

OMe

R' R

NEt3

completed cycloaddition

HNEt3 + PF 6-

INT4 R'

HNEt3 + PF6-

b

R O

N

9

O

INT1

N Cu

OMe O

a O 2N

1

OMe

N Cu

R''

R' R

9

O

CO2Me

N H 3

NEt3

O

R''

O 2N

OMe

high temperature R''

2

O 2N R' R 9

R'' N Cu

OMe O

INT5

INT2 d

We next examined the origins of the unexpected change in diastereoselectivity on going from aldimines 1a-d to ketimines 1e-g. DFT calculations10 on the transition structures associated with the conjugate addition of azomethine ylides derived from aldimine 1b and ketimine 1e in the presence of Cu(I) 12 ACS Paragon Plus Environment

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and our previously developed chiral ligand 9 were carried out using the ONIOM methodology11 at the M06/6-31++G** &LANL2DZ//ONIOM(B3LYP/LANL2DZ:PM6) level12,13 of theory (see the Computational Methods section and the Supporting Information for additional details). According to our results, in syn-TS1 the nitro group of nitroalkene 2a occupies a distal position with respect to the Cu(I) center thus minimizing the electrostatic repulsion between the nitro and methoxycarbonyl groups. In addition, in this saddle point there is a stabilizing π−stacking interaction between the aryl group of Michael acceptor 2a and one phenyl group of the diphenylphosphine moiety, with a calculated Ph(9)-Ph(2a) distance of 3.3 Å. In contrast, saddle point anti-TS1 involves a steric repulsion between the nitro group of 2a and the Ph2P-cyclopeentadienyl moiety of 9, which is not compensated by the attractive Coulombic interaction between the nitro group (with a charge of -0.42 a. u.) and the positively charged (+0.48 a. u.) Cu(I) center. These different interactions result in the preferential formation of syn-4a (Figure 1A) from the reaction between imine 1b and nitroalkene 2a, in nice agreement with the experimental results. We also located and characterized transition structure syn-TS2, associated with the reaction between imine 1e and nitroalkene 2a. In this saddle point, the previously mentioned Ph(2a)-Ph(9) π−stacking cannot overcome the steric clash between the nitro group of 2a and one of the phenyl groups of the ketimine moiety of 1e, which cannot be coplanar with respect to the other one (Figure 1B) As a consequence, transition structure anti-TS2, which is sterically less congested and incorporates the stabilizing Cu(I)-NO2 interaction, is 5.9 kcal/mol lower in energy than syn-TS2 . Therefore, in this latter case the formation of Michael adduct anti-4a via anti-TS2 is preferred (Figure 1B). It is noteworthy that, since our chiral catalytic ligand 9 promotes in both cases the blockage of the same prochiral face of the intermediate azomethine ylide, the configuration of the carbon atom incorporating the α−amino group is the same in both cases (see the geometries and relative energies of the other four possible transition structures in Table S1 and Figure S4 of the Supporting Information) . Thus, D-ester 9 promotes the for13 ACS Paragon Plus Environment


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mation of L-esters syn- and anti-4. It is important to emphasize, however, that the stereochemical outcome of this reaction is the consequence of a complex trade off between stabilizing and repulsive nonbonding interactions.

Figure 1. Fully optimized geometries (M06/6-31++G**&LANL2DZ//ONIOM(B3LYP/LANL2DZ:PM6) level of theory) of transition structures syn-TS1 and anti-TS1 (A) and syn-TS2 and anti-TS2 (B). These structures are formed from nitroalkenes 2a and imines 1b and 1e, respectively in the pres-


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ence of chiral catalytic ligand 9. Both saddle points lead preferentially to Michael adducts syn-4a and anti-4a, respectively. Bond distances are given in Å. 2.2. Completed (3 + 2) cycloadditions. Once we prepared conjugate adducts syn- and anti-4a-h, we studied their conversion into γ−lactams 6 (Scheme 2). Catalytic hydrogenation of γ−nitro−α−amino esters 4a-c resulted in the spontaneous and quantitative cyclization of the intermediate α,γ−diamino esters to form γ−lactams cis- and trans-6a-c (Scheme 6). Since the cyclization process takes place with double retention of configuration at the two chiral centers, syn-esters 4 give rise to the corresponding translactams, whereas the analogue anti-esters yield lactams cis-6a-c. From α−amino−γ−lactams 6a-c the corresponding imines 10a-e were obtained also in quantitative yield (Scheme 6). These imines are the precursors of the corresponding in situ formed azomethine ylides INT3 that should lead to the corresponding bis-spiropyrrolidines 5 via completed (3 + 2) cycloadditions (Scheme 2). Scheme 6. Synthesis of γ−Lactams 6a-c and 10a-e γ−



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O 2N

O2N R1

H 2N

R1

CO 2Me

H 2N

syn-4a-c

Page 16 of 47

4a: R1=Ph 4b: R1 =4-F-C 6H 4 4c: R1=4-MeO-C6H 4

CO 2Me

anti-4a-c

H 2, 10 bar, 65 ºC Ni-Raney, MeOH (quant.) R1

H 2N O

R1

H 2N O

N H

N H cis-6a-c

trans-6a-c

8a: R 2=Ph 8b: R 2=4-MeO-C 6H 4 8c: R 2=4-F-C 6H 4

R2

CH 2Cl 2, MgSO 4 r. t., 16 h O (quant.) 8a-c

R2

R2 R1

N O

N H

trans-10a-e

6a: R1 =Ph 6b: R1 =4-F-C 6H 4 6c: R1 =4-MeO-C 6H 4

R1

N O

N H

10a: R1 =R 2=Ph 10b: R1 =4-MeO-C6H 4; R 2=Ph 10c: R1 =4-F-C 6H 4; R 2=Ph 10d: R1 =Ph; R 2=4-MeO-C 6H 4 10e: R1 =Ph; R 2=4-F-C6H 4

cis-10a-e

We selected π−deficient alkenes gathered in Chart 1 as suitable dipolarophiles for (3 + 2) cycloadditions involving azomethine ylides derived from γ−lactams cis- and trans-10a-e. These dipolarophiles include alkenes possessing one (2a, 7c and 7d) or two (7a, 7b) electron-withdrawing groups. From the stereochemical standpoint, cis (7b) and trans-alkenes (2a, 7a) were selected in order to monitor the retention of configuration of the dipolarophiles, despite the stepwise nature of these completed (3 + 2) cycloadditions. Finally, these dipolarophiles permitted to assess the endo or exo diastereoselectivity of the corresponding 1,3-dipolar reactions depending upon the cis or trans disposition between the R5 and R6 groups of spiro cycloadducts 5, respectively (Scheme 2).


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Chart 1. Dipolarophiles Used in (3 + 2) Cycloadditions involving Azomethine Ylides Derived from γ−Lactams 10a-e γ−

Reaction between imines 10a-e with either nitroalkene 2a and dipolarophiles 7a-d resulted in the fully regio- and disatereoselective formation of spiro cycloadducts 5a-i (Schemes 7 and 8).14 In these completed (3 + 2) cycloadditions, silver acetate in the presence of triethylamine promoted efficiently the formation of the corresponding N-metallated azomethine ylides. In all cases, retention of configuration of the dipolarophiles was observed and the corresponding endo (3+2) cycloadducts were obtained. The only exception was observed when (E)-1,2-bis(phenylsulfonyl)ethene 7a was used as dipolarophile. In this case exo-cycloadduct 5a was obtained as the sole reaction product with complete enantiocontrol, as proved by HPLC and X-ray diffraction analysis14 (Scheme 7). Scheme 7. Synthesis of Spiro Compounds 5a-i from trans-γ− γ−Lactams 10a-e γ−



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R2

O

R3

R4 R1

N N H

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R4 R1

R2

R 3 2a, 7a-d

HN

AgOAc, NEt 3 toluene, r. t.

O

N H 5a-i

trans-10a-e O

Ph HN

SO 2Ph SO 2Ph Ph

O

Ph O

HN

HN

O

O

5d (61 %) F

O

HN O

N H 5c (71 %)

F MeO

NO 2 HN O

N H 5e (51 %) CO2Me

NO 2 HN

Ph Ph

Ph

Ph

Ph

N H

NO 2

N H 5b (88 %) NO 2

OMe Ph

Ph

HN

N H 5a (85 %)

NO 2 Ph

NMe O

Ph Ph Ph N H 5g (70 %)

O

N H 5f (68 %)

CO 2t-Bu Ph

HN

Ph Ph

N H 5h (85 %)

Ph

Ph

HN O

N H 5i (75 %)

It is interesting to note that in all the cases studied only one enantiomer was obtained depending on the cis or trans configuration of the corresponding imino γ−lacman 10. Therefore, both our catalyst 9 (NH-D-EhuPhos) and the starting aldimines 1b-d and ketimine 1e determine completely the configuration of bis-spiropyrrolidines 5. In particular, aldimine 1b gives rise to spiro compounds 5a-i through the 1b → syn-4a-c → trans-10a-e → 5a-i sequence (Scheme 7). In contrast, ketimine 1e permits to obtain the enantiomeric spiro compounds ent-5 by means of the 1e → anti-4a-c → cis-10a-e → ent-5a-i sequence (Scheme 8). In other words, our catalytic system based on enantiopure ligand 9 determines the enantiopurity of the final compounds, whereas the starting aldimine or ketimine azomethine precursors are responsible for the enantiodivergence of the whole sequence. The origins of this enantiodivergent behaviour are discussed below.


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Scheme 8. Synthesis of spiro compounds ent-5b-g,i from cis-γ− γ−lactams 10a-e γ− R2 R1

N O

R3

R4 R3 2a, 7a-d

HN

AgOAc, NEt3 toluene, r. t.

N H

R4 R1

R2 O

N H

ent-5b-g,i

cis-10a-e O NMe O Ph O

Ph Ph

Ph

Ph

HN

NO2

NO2 HN O

N H

Ph HN O

N H

N H ent-5d (62 %)

ent-5c (78 %)

ent-5b (85 %)

F MeO

NO2

OMe Ph

NO2

Ph

Ph HN O

Ph Ph

HN O

N H

N H

ent-5e (58 %) F

ent-5f (71 %) CO2t-Bu

NO2 Ph Ph

HN O

Ph

N H ent-5g (56 %)

Ph

HN O

N H ent-5i (72 %)

As a representative case study of these completed (3 + 2) cycloadditions, we performed additional DFT calculations (M06/6-31++G*&LanL2DZ//B3LYP/6-31+G*&LANL2DZ level of theory) associated with the stepwise transformation of azomethine ylide INT3a into cycloadduct 5c by reaction with nitrostyrene 2a in the presence of silver acetate. According to our calculations, interaction between 1,3-dipole INT3a and dipolarophile 2a leads to a reactive complex RC, from which zwitterionic intermediate INT4a is formed via a conjugated addition with no significant energy barrier. Therefore, these completed (3 + 2) cycloadditions are also stepwise. The chief geometric features of transition structures endo-TS3a and endo-TS4a, as well as the energy profile associated with this (3 + 2) stepwise cycload19 ACS Paragon Plus Environment


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dition are gathered in Figure 2A. Our results indicate that the endo selectivity experimentally observed stems from the interaction between the nitro group and the metallic centre along the entire reaction coordinate. The stepwise nature of the cycloaddition is demonstrated by the characterization of endoINT4a as true a local minimum. The second activation energy associated with the formation of the C4C5 bond of the pyrrolidine through endo-TS4a was computed to be also very low (Figure 2A) and can be interpreted as a metal-assisted intramolecular Mannich-Henry reaction.

Figure 2. Enantiodivergent formation of spiro bispyrrolidines 5c (A) and ent-5c (B) from trans-10a (A) and

cis-10a

(B),

respectively.

The

reaction

profile,

computed

at

the

M06(PCM)/6-

31++G*&LANL2DZ//B3LYP(PCM)/6-31+G*&LANL2DZ level of theory is shown in (A). Internuclear distances and energies are given in Å and kcal/mol, respectively. Numbers in parentheses correspond


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to relative energies (in kcal/mol) with respect to separate reactants 2a and INT3a. Red asterisks emphasize the temporary destruction of chiral information at C2. It is interesting to note that formation of azomethine ylides INT3 involves the temporary destruction of the chiral information borne by the α−carbon of the corresponding γ−lactam 10. Therefore, during the completed (3 + 2) cycloaddition process, the β−carbon is the only source of chiral induction (Schemes 7 and 8). In principle, the dipolarophile should interact with the azomethine ylide along the opposite face that incorporates the R1 substituent (the phenyl group highlighted in grey in Figure 2A). Our calculations indicate that the alternative transition structures are of significantly higher energy, thus resulting in complete enantiocontrol (see the Supporting Information for additional details). This means that cis- and trans−γ−lactams 10 should yield enantiomeric spiro (3 + 2) cycloadducts 5 (Figure 2B). 2.3. Preliminary biological studies. In order to explore the potential of these spiranic scaffolds in medicinal chemistry, several bis-spiropyrrolodines 5 were tested15 against different biological targets of relevance in oncology, neurosciences and cardiovascular diseases. In several cases moderate inhibitory activity was found. It was found that cycloadduct 5c (Scheme 7) showed up to ca. 41% K-Ras Wnt synthetic lethal activity16 against cell line Colo 320 Kras SL at 200 nM concentration. This activity has potential interest in the development of selective therapies against colon cancer. In addition, micromolar concentrations of ent-5b (10 µM) and ent-5c (100 µM) inhibited histone methyl transferases SetD817 (23.6 %) and EZH218 (32 %), respectively (Scheme 8). Inhibition of both epigenetic enzymes is of interest in the treatment of different types of cancer17,18. Aside these inhibitory activities, 5c was found to be a moderate Nav1.7 sodium channel antagonist, with a potency of 28 % at 3 µM. Since Nav1.7 is expressed in peripheral nervous system and sympathetic ganglia, it has been suggested that inhibitors of this kind of voltage-gated sodium ion channels possess therapeutic potential in the treatment of chronic pain.19 Finally, in vitro data indicate that 5b (Scheme 7) inhibits proprotein convertase subtilisin kexin



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type 9 (PCSK9) with IC50=5 µM. This result is interesting given the relevance of PCSK9 in the regulation of cholesterol homeostasis via low density lipoproteins (LDL).20 Scheme 9. Synthesis and Biological Activity of Hydroxamic Acid 14 O R2

CO 2R1 Ph

Ph

Ph HN O

TFA, CH 2Cl 2

O

CO 2Me

NH 3 Cl

NH Ph

HN

12 O N TBTU, NEt 3, DMF H 5i (R1 =t-Bu) HONH 3Cl , NaOMe 11 (R1 =H)

N H 13 (R 2=OMe) 14 (R 2=NHOH) EC 50=9.2 µM (HeLa nuclear extract)

We also designed hydroxamic acid 14 as a potential histone deacetylases (HDAC) inhibitor (Scheme 9). Histone deacetylases are very relevant epigenetic enzymes whose therapeutic interest in cancer therapy is well recognized. 21 In previous work we have demonstrated the potential of 1H-pyrrole derivatives as potent HDAC paninhibitors and as chemotherapeutic reagents against different types of human cancer. 22 Acidic cleavage of the ester moiety in 5i followed by amide coupling between the resulting carboxylic acid 11 and amino ester hydrochloride 12 yielded ester 13. Hydroxamic acid 14 was readily obtained by reaction between 13 and hydroxymethyl amine hydrochloride. Interestingly, compound 14 showed low micromolar activity in HeLa nuclear extracts (Scheme 9). All these results show that, although certainly further development is required, spiro compounds 5 (in both enantiomeric forms) constitute promising scaffolds in oncology, neuroscience and biomedicine. 3. Conclusions In this paper we show that enantiopure bis-spiropyrrolidines 5 can be prepared from readily available precursors by means of a highly efficient and enantiodivergent procedure based on a sequence of inter22 ACS Paragon Plus Environment

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rupted and completed (3 + 2) cycloadditions between metallated azomethine ylides and nitroalkenes or other dipolarophiles. A convenient choice of the substituents in the starting 1,3-dipole permits to stop the first (3 + 2) cycloadditions at the first step. Chiral catalytic ligand 9, previously described by our group, is the only source of chiral induction. After acidic hydrolytic work-up and catalytic reduction of the nitro group of the corresponding cycloadducts, enantiopure α−amino−γ−lactams are obtained with excellent yields. Bis-spiropyrrolidines 5 can be obtained in both enantiomerically pure forms via completed (3 + 2) cycloadditions involving suitable dipolarophiles and the imines derived from cis- or trans−γ−lactams 10. Finally, the potential of these enantiopure rigid spiro compounds in Medicinal Chemistry has been explored. We think that this spiro scaffold as well as the concept of interrupted/completed stepwise cycloaddition can be extended to other enantiopure densely substituted compounds. 4. Experimental Section General experimental procedures. All reactions were carried out under an atmosphere of argon unless otherwise stated. All melting points are uncorrected. Flash column chromatographies were carried out with silica gel 60 (0.040-0.063mm) eluting with ethyl acetate/hexane. Infrared spectra were recorded on a FT-IR spectrometer. 1H,

13

C and

19

F NMR spectra were recorded at 500 MHz or 400 MHz and 126

MHz or 101 and 375 MHz, respectively in CDCl3 and DMSO solvent with tetramethylsilane as internal reference TMS. Optical rotations were measured at the wavelength of 589 nm (sodium D line). The absolute configurations of the known products were determined by comparing optical rotation values with the literature data. The HPLC chromatograms of the racemic and enantiomerically enriched products were performed using Daicel Chiralpak IA, IB, IC and AS-H columns. HRMS analyses were carried out using the electron impact (EI) mode at 70 eV or by QTOF using electrospray ionization (ESI) mode. All solvents were of p.a. quality and were dried by standard procedures prior to use if necessary. The commercially available reagents (nitroalkenes 2a-f, aldehydes 8a-b, aminoesters 15a-c and imino esters 23 ACS Paragon Plus Environment


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1f,g) were used without further purification. Chiral ligand 9 was prepared according to the previously published procedures.8 General procedure for the preparation of α-iminoesters 1a-d. To a solution of the corresponding αaminoester hydrochloride 15a-c (3.0 mmol) in dry CH2Cl2 (5 ml), MgSO4 and Et3N (3.0 mmol) were added at room temperature. The resulting mixture was stirred at the same temperature for 1 hour. Then the aldehyde 8a or 8b (2.3 mmol) was added, and the resulting mixture was stirred for 18 hours. Then the MgSO4 was filtered off and the organic layer washed three times with water, dried over anhydrous Na2SO4, and evaporated under reduced pressure to afford the pure product, which was used in the next step without further purification. Methyl (E)-N-benzylideneglycinate (1a). The title compound3a was obtained as a colorless oil (342 mg, 1.93 mmol, 84 %). 1H-NMR (500 MHz, CDCl3) δ = 8.29 (s, 1H), 7.80 – 7.75 (m, 2H), 7.47 – 7.38 (m, 3H), 4.42 (s, 2H), 3.78 (s, 3H). Methyl (E)-N-(4-methoxybenzylidene)-glycinate (1b). The title compound3a was obtained as a yellow solid (329 mg, 1.59 mmol, 69 %). 1H-NMR (500 MHz, CDCl3) δ = 8.22 (s, 1H), 7.72 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 4.38 (s, 2H), 3.84 (s, 3H), 3.77 (s, 3H). Ethyl (E)-N-(4-methoxybenzylidene)-glycinate (1c). The title compound3a was obtained as a yellow oil (372 mg, 1.68 mmol, 73 %). 1H-NMR (500 MHz, CDCl3) δ = 8.17 (s, 1H), 7.69 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 4.32 (s, 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H). tert-Butyl (E)-N-(4-methoxybenzylidene)-glycinate (1d). The title compound3a was obtained as a yellow solid (298 mg, 1.20 mmol, 52 %). 1H-NMR (500 MHz, CDCl3) δ = 8.16 (s, 1H), 7.70 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 4.25 (d, J = 0.7 Hz, 2H), 3.82 (s, 3H), 1.47 (s, 9H). Methyl 2-[(diphenylmethylene)amino]acetate (1e). A mixture of diphelymethanimine (2.72 g, 15.0 mmol), glycine methyl ester hydrochloride (1.88 g,15.0 mmol) and MgSO4 in dry CH2Cl2 (60 ml) was 24 ACS Paragon Plus Environment

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stirred at room temperature for 24 hours. The solid was filtered off and the fíltrate was concentrated under reduced pressure. The residue was dissolved in Et2O and washed three times with water, dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford the corresponding pure imine, which was used in the next step without further purification. The title compound3a was obtained as a pale yellow oil (3.08 g, 12.15 mmol, 81%). 1H-NMR (500 MHz, CDCl3) δ = 7.60 – 7.56 (m, 2H), 7.45 – 7.35 (m, 4H), 7.26 (t, J = 7.5 Hz, 2H), 7.11 (dd, J = 7.4, 1.5 Hz, 2H), 4.15 (s, 2H), 3.67 (s, 3H). General procedure for the enantioselective conjugate addition reactions between α-iminoesters 1bg and nitroalkenes 2a-f. A solution of α-iminoester 1b-g (0.45 mmol), chiral ligand 9 (4.95 µmol) and Cu(CH3CN)4PF6 (4.50 µmol) in 2.0 ml of dry THF was stirred at room temperature for 15 minutes and for additional 15 minutes at -60 ºC. Then, a precooled (-60 ºC) solution of the corresponding nitroalkene 2a-f (0.50 mmol) in 1.0 ml of dry THF and triethylamine (3.2 µl, 0.023 mmol) were successively added (the reaction was monitored by TLC). Once the starting material was consumed HCl 1N (0.9 ml) was added at -60 ºC and the reaction was allowed to warm to room temperature. The mixture was stirred for 1 hour and after evaporation of THF under reduced pressure, the residue was washed three times with Et2O. The aqueous solution was rendered alkaline by addition of saturated aqueous solution of NaHCO3 (until pH=8.0) and the product was extracted with CH2Cl2 (several times). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to give the corresponding pure product anti- or syn-4a-h. The enantiomeric excesses were determined by comparison with the chromatogram recorded for the racemic mixture of the corresponding product. (2S,3R)-Methyl 2-amino-4-nitro-3-phenylbutanoate (syn-4a). The title compound was obtained as a white waxy solid. (90 mg, 0.38 mmol, 84%). M. p.: 40-42 ºC. IR (neat) 3387, 3326, 1735, 1546, 1378 cm-1. 1H-NMR (500 MHz, CDCl3) δ = 7.28 – 7.20 (m, 3H), 7.10 (dd, J = 7.4, 1.5 Hz, 2H), 5.00 (dd, J = 13.1, 8.2 Hz, 1H), 4.70 (dd, J = 13.1, 6.8 Hz, 1H), 3.96 (td, J = 7.5, 4.5 Hz, 1H), 3.73 (d, J = 4.1 Hz, 1H), 3.61 (s, 3H), 1.44 (bs, 2H). 13C-NMR (126 MHz, CDCl3) δ = 174.1, 135.1, 129.1, 128.6, 128.4, 25 ACS Paragon Plus Environment


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76.9, 56.0, 52.4, 46.5. [α]24D = +25.7 (c 1.00, CHCl3), >99% ee. HPLC: Daicel Chiralpak IB, isopropanol/hexane 10/90, flow rate = 1.0 ml/min, tr: 19.3 min (2S,3R) and 25.8 min (2R,3S), 210 nm. Anal. Calcd. For C11H14N2O4: C, 55.5; H, 5.9; N, 11.8; Found: C, 55.7; H, 6.2; N, 11.8. (2S,3S)-Methyl 2-amino-4-nitro-3-phenylbutanoate (anti-4a). The title compound was obtained as a white solid (95 mg, 0.40 mmol, 89%). M. p.: 61-62 ºC. IR (neat) 3365, 3276, 1728, 1537, 1379 cm-1. 1

H-NMR (500 MHz, CDCl3) δ = 7.38 – 7.23 (m, 3H), 7.21 (d, J = 7.0 Hz, 2H), 5.05 (dd, J = 13.3, 5.7

Hz, 1H), 4.77 (dd, J = 13.3, 8.9 Hz, 1H), 3.81 (dd, J = 14.1, 8.0 Hz, 1H), 3.69 (d, J = 7.6 Hz, 1H), 3.54 (s, 3H), 1.62 (bs, 2H). 13C-NMR (126 MHz, CDCl3) δ = 173.9, 136.5, 128.9, 128.2, 127.9, 77.0, 57.8, 52.0, 47.7. [α]24D = +9.9 (c 1.00, CHCl3), 95% ee. HPLC: Daicel Chiralpak IC, iso-propanol/hexane 20/80, flow rate = 1.0 ml/min, tr: 25.3 min (2S,3S) and 27.7 min (2R,3R), 210 nm. Anal. Calcd. For C11H14N2O4: C, 55.5; H, 5.9; N, 11.8; Found: C, 55.5; H, 6.2; N, 11.8. (2S,3R)-Methyl 2-amino-3-(4-fluorophenyl)-4-nitrobutanoate (syn-4b). The title compound was obtained as a yellow oil (98 mg, 0.38 mmol, 85%). IR (neat) 3391, 3329, 1735, 1547, 1377 cm-1. 1H-NMR (500 MHz, CDCl3) δ = 7.11 (dd, J = 8.5, 5.3 Hz, 2H), 6.94 (t, J = 8.6 Hz, 2H), 4.96 (dd, J = 13.0, 8.0 Hz, 1H), 4.68 (dd, J = 13.0, 7.1 Hz, 1H), 3.96 (td, J = 7.4, 4.2 Hz, 1H), 3.73 (bs, 1H), 3.61 (s, 3H), 1.47 (bs, 2H). 13C-NMR (126 MHz, CDCl3) δ = 173.8, 162.9 (d, J = 247.6), 130.8 (d, J = 2.9), 130.2 (d, J = 8.1), 116.1 (d, J = 21.4), 77.0, 55.8, 52.6, 45.7. [α]24D = +22.1 (c 1.00, CHCl3), >99% ee. HPLC: Daicel Chiralpak IA, iso-propanol/hexane 15/85, flow rate = 1.0 ml/min, tr: 12.0 min (2S,3R) and 15.1 min (2R,3S), 210 nm. Anal. Calcd. For C11H13FN2O4: C, 51.6; H, 5.1; N, 10.9; Found: C, 51.2; H, 5.2; N, 10.9. (2S,3S)-Methyl 2-amino-3-(4-fluorophenyl)-4-nitrobutanoate (anti-4b). The title compound was obtained as a pale yellow oil (94 mg, 0.37 mmol, 82%). IR (neat) 3389, 3324, 1732, 1547, 1377 cm-1. 1HNMR (500 MHz, CDCl3) δ = 7.21 (dd, J = 8.1, 5.3 Hz, 2H), 7.02 (t, J = 8.5 Hz, 2H), 5.05 (dd, J = 13.3, 5.4 Hz 1H), 4.73 (dd, J = 13.2, 9.3 Hz, 1H), 3.80 (dt, J = 8.6, 5.7 Hz, 1H), 3.65 (d, J = 7.9 Hz, 1H), 3.56 26 ACS Paragon Plus Environment

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(s, 3H), 1.71 (bs, 2H). 13C-NMR (126 MHz, CDCl3) δ = 173.7, 162.3 (d, J = 247.3), 132.0 (d, J = 3.0), 129.5 (d, J = 8.2), 115.7 (d, J = 21.5), 77.0, 57.6, 52.0, 46.9. [α]24D = +4.5 (c 1.00, CHCl3), 90% ee. HPLC: Daicel Chiralpak IC, iso-propanol/hexane 20/80, flow rate = 1.0 ml/min, tr: 20.6 min (2S,3S) and 22.6 min (2R,3R), 210 nm. Anal. Calcd. For C11H13FN2O4: C, 51.6; H, 5.1; N, 10.9; Found: C, 51.4; H, 5.1; N, 10.9. (2S,3R)-Methyl 2-amino-3-(4-methoxyphenyl)-4-nitrobutanoate (syn-4c). The title compound was obtained as a white solid (103 mg, 0.38 mmol, 85%). M. p.: 76-78 ºC. IR (neat) 3383, 3324, 1729, 1551, 1375 cm-1. 1H-NMR (500 MHz, CDCl3) δ = 7.03 (d, J = 8.6 Hz, 2H), 6.77 (d, J = 8.7 Hz, 2H), 4.96 (dd, J = 13.0, 8.1 Hz, 1H), 4.66 (dd, J = 13.0, 7.0 Hz, 1H), 3.92 (td, J = 7.5, 4.4 Hz, 1H), 3.72 – 3.67 (m, 4H), 3.62 (s, 3H), 1.46 (s, 2H).

13

C-NMR (126 MHz, CDCl3) δ = 174.0, 159.6, 129.3, 126.6, 114.4,

77.0, 55.9, 55.3, 52.3, 45.6. [α]24D = +21.2 (c 1.00, CHCl3), >99% ee. HPLC: Daicel Chiralpak IB, isopropanol/hexane 15/85, flow rate = 1.0 ml/min, tr: 18.8 min (2S,3R) and 23.5 min (2R,3S), 210 nm. Anal. Calcd. For C12H16N2O5: C, 53.7; H, 6.0; N, 10.4; Found: C, 53.9; H, 6.1; N, 10.5. (2S,3S)-Methyl 2-amino-3-(4-methoxyphenyl)4-nitrobutanoate (anti-4c). The title compound was obtained as a yellow solid (101 mg, 0.38 mmol, 84%). M. p.: 93-95 ºC. IR (neat) 3383, 3323, 1731, 1546, 1378 cm-1. 1H-NMR (500 MHz, CDCl3) δ = 7.13 (d, J = 8.3 Hz, 2H), 6.85 (d, J = 8.3 Hz, 2H), 5.03 (dd, J = 12.8, 4.8 Hz, 1H), 4.73 (dd, J = 12.7, 9.0 Hz, 1H), 3.78 (s, 4H), 3.71 – 3.62 (m, 1H), 3.56 (s, 3H), 1.62 (s, 2H). 13C-NMR (126 MHz, CDCl3) δ = 173.8, 159.1, 128.8, 127.8, 114.0, 77.1, 57.6, 54.9, 51.9, 46.8. [α]24D = +5.0 (c 1.00, CHCl3), 90% ee. HPLC: Daicel Chiralpak IC, iso-propanol/hexane 10/90, flow rate = 1.0 ml/min, tr: 74.1 min (2S,3S) and 80.8 min (2R,3R), 210 nm. Anal. Calcd. For C12H16N2O5: C, 53.7; H, 6.0; N, 10.4; Found: C, 54.1; H, 6.1; N, 10.5. (2S,3R)-Methyl 2-amino-3-(4-methylphenyl)-4-nitrobutanoate (syn-4d). The title compound was obtained as a waxy solid (98 mg, 0.39 mmol, 86%). M. p.: 43-45 ºC. IR (neat) 3409, 3342, 1737, 1541, 1380 cm-1. 1H-NMR (500 MHz, CDCl3) δ = 7.05 (d, J = 7.9 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 4.97 (dd, 27 ACS Paragon Plus Environment


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J = 13.0, 8.1 Hz, 1H), 4.68 (dd, J = 13.0, 6.9 Hz, 1H), 3.93 (dt, J = 11.6, 5.9 Hz, 1H), 3.70 (d, J = 2.7 Hz, 1H), 3.62 (s, 3H), 2.24 (s, 3H), 1.42 (bs, 2H). 13C-NMR (126 MHz, CDCl3) δ = 174.2, 138.3, 131.8, 129.8, 128.2, 77.0, 56.0, 52.4, 46.1, 21.2. [α]24D = +22.9 (c 1.00, CHCl3), >99% ee. HPLC: Daicel Chiralpak IB, iso-propanol/hexane 15/85, flow rate = 1.0 ml/min, tr: 12.8 min (2S,3R) and 16.6 min (2R,3S), 210 nm. Anal. Calcd. For C12H16N2O4: C, 57.1; H, 6.4; N, 11.1; Found: C, 57.1; H, 6.5; N, 11.2. (2S,3S)-Methyl 2-amino-3-(4-methylphenyl)-4-nitrobutanoate (anti-4d). The title compound was obtained as a white solid (81 mg, 0.32 mmol, 71%). M. p.: 55-57 ºC. IR (neat) 3386, 3323, 1732, 1547, 1377 cm-1. 1H-NMR (500 MHz, CDCl3) δ = 7.13 (d, J = 7.6 Hz, 2H), 7.09 (d, J = 7.7 Hz, 2H), 5.02 (dd, J = 13.2, 5.6 Hz, 1H), 4.75 (dd, J = 13.1, 8.9 Hz, 1H), 3.79 (dd, J = 13.7, 7.5 Hz, 1H), 3.69 (d, J = 6.4 Hz, 1H), 3.57 (s, 3H), 2.31 (s, 3H), 1.64 (bs, 2H). 13C-NMR (126 MHz, CDCl3) δ = 173.8, 137.8, 133.1, 129.5, 127.6, 77.0, 57.7, 52.0, 47.2, 20.9. [α]24D = +4.6 (c 1.00, CHCl3), 94% ee. HPLC: Daicel Chiralpak IC, iso-propanol/hexane 8/92, flow rate = 1.0 ml/min, tr: 51.8 min (2S,3S) and 57.2 min (2R,3R), 210 nm. Anal. Calcd. For C12H16N2O4: C, 57.1; H, 6.4; N, 11.1; Found: C, 57.1; H, 6.4; N, 11.4. (2S,3R)-Methyl 2-amino-3-(2-fluorophenyl)-4-nitrobutanoate (syn-4e). The title compound was obtained as a pale yellow oil (92 mg, 0.36 mmol, 80%). IR (neat) 3390, 3330, 1735, 1548, 1377 cm-1. 1HNMR (500 MHz, CDCl3) δ = 7.27 – 7.15 (m, 2H), 7.05 (t, J = 7.3 Hz, 1H), 7.01 – 6.96 (m, 1H), 4.99 (dd, J = 13.3, 7.8 Hz, 1H), 4.71 (dd, J = 13.3, 7.0 Hz, 1H), 4.25 (dd, J = 12.0, 7.2 Hz, 1H), 3.77 (d, J = 3.0 Hz, 1H), 3.63 (s, 3H), 1.46 (s, 2H).

13

C-NMR (126 MHz, CDCl3) δ = 173.9, 160.6 (d, J = 246.7),

129.9 (d, J = 8.6), 129.5 (d, J = 3.6), 124.4 (d, J = 3.4), 122.1 (d, J = 14.3), 115.9 (d, J = 22.7), 76.0, 55.0, 52.3, 39.9. [α]24D = +44.0 (c 1.00, CHCl3), >99% ee. HPLC: Daicel Chiralpak AS-H, isopropanol/hexane 15/85, flow rate = 1.0 ml/min, tr: 27.4 min (2R,3S) and 40.3 min (2S,3R), 210 nm. Anal. Calcd. For C11H13FN2O4: C, 51.6; H, 5.1; N, 10.9; Found: C, 51.7; H, 5.0; N, 10.7.


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(2S,3S)-Methyl 2-amino-3-(2-fluorophenyl)-4-nitrobutanoate (anti-4e). The title compound was obtained as a yellow oil (108 mg, 0.42 mmol, 94%). IR (neat) 3391, 3323, 1732, 1548, 1377 cm-1. 1HNMR (500 MHz, CDCl3) δ = 7.20 (dd, J = 16.5, 11.5 Hz, 1H), 7.13 (t, J = 7.1 Hz, 1H), 7.09 – 6.94 (m, 2H), 5.05 (dd, J = 13.4, 5.3 Hz, 1H), 4.76 (dd, J = 13.4, 8.8 Hz, 1H), 3.89 (dd, J = 13.8, 8.3 Hz, 1H), 3.75 (d, J = 8.4 Hz, 1H), 3.43 (s, 3H), 1.60 (s, 2H). 13C-NMR (126 MHz, CDCl3) δ = 174.0, 161.0 (d, J = 246.8), 130.4 (d, J = 4.3), 130.0 (d, J = 8.6), 124.5 (d, J = 3.0), 123.4 (d, J = 13.5), 116.0 (d, J = 22.2), 76.1, 56.3, 52.1, 43.6. [α]26D = +15.8 (c 1.00, CHCl3), 93% ee. HPLC: Daicel Chiralpak IC, isopropanol/hexane 10/90, flow rate = 1.0 ml/min, tr: 33.1 min (2S,3S) and 35.9 min (2R,3R), 210 nm. Anal. Calcd. For C11H13FN2O4: C, 51.6; H, 5.1; N, 10.9; Found: C, 51.3; H, 5.3; N, 10.9. (2S,3R)-Methyl 2-amino-3-(2-furyl)-4-nitrobutanoate (syn-4f). The title compound was obtained as a brown oil (77 mg, 0.34 mmol, 75%). IR (neat) 3385, 3339, 1736, 1549, 1376 cm-1. 1H-NMR (500 MHz, CDCl3) δ = 7.29 (dd, J = 1.8, 0.6 Hz, 1H), 6.24 (dd, J = 3.2, 1.9 Hz, 1H), 6.10 (d, J = 3.2 Hz, 1H), 4.90 (dd, J = 13.4, 7.5 Hz, 1H), 4.73 (dd, J = 13.4, 7.2 Hz, 1H), 4.19 (dd, J = 10.8, 7.3 Hz, 1H), 3.67 (s, 4H), 1.55 (bs, 2H).

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C-NMR (126 MHz, CDCl3) δ = 173.9, 148.8, 143.0, 110.5, 108.6, 75.0, 55.2, 52.5,

40.7. [α]24D =+37.2 (c 1.00, CHCl3), 95% ee. HPLC: Daicel Chiralpak IC, iso-propanol/hexane 20/80, flow rate = 1.0 ml/min, tr: 21.8 min (2S,3R) and 25.9 min (2R,3S), 210 nm. Anal. Calcd. For C9H12N2O5: C, 47.4; H, 5.3; N, 12.3; Found: C, 46.6; H, 5.5; N, 12.1. (2S,3S)-Methyl 2-amino-3-(2-furyl)-4-nitrobutanoate (anti-4f). The title compound was obtained as a yellow oil (83 mg, 0.36 mmol, 81%). IR (neat) 3390, 3323, 1732, 1549, 1376 cm-1. 1H-NMR (500 MHz, CDCl3) δ = 7.37 (dd, J = 1.9, 0.7 Hz, 1H), 6.31 (dd, J = 3.1, 1.9 Hz, 1H), 6.21 (d, J = 3.1 Hz, 1H), 4.93 (dd, J = 13.5, 5.4 Hz, 1H), 4.81 (dd, J = 13.5, 8.6 Hz, 1H), 3.99 (dt, J = 8.4, 6.2 Hz, 1H), 3.81 (d, J = 6.7 Hz, 1H), 3.68 (s, 3H), 1.65 (bs, 2H).

13

C-NMR (126 MHz, CDCl3) δ = 173.5, 149.8, 142.8, 110.5,

108.4, 75.0, 56.0, 52.4, 41.7. [α]24D = +14.6 (c 1.00, CHCl3), 96% ee. HPLC: Daicel Chiralpak IA, isopropanol/hexane 5/95, flow rate = 1.0 ml/min, tr: 33.1 min (2S,3S) and 39.0 min (2R,3R), 210 nm. Anal. Calcd. For C9H12N2O5: C, 47.4; H, 5.3; N, 12.3; Found: C, 47.3; H, 5.5; N, 12.2. 29 ACS Paragon Plus Environment


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(2S,3R)-Ethyl 2-amino-4-nitro-3-phenylbutanoate (syn-4g). The title compound was obtained as a colorless oil (96 mg, 0.38 mmol, 85%). IR (neat) 3390, 3328, 1730, 1547, 1377 cm-1. 1H-NMR (500 MHz, CDCl3) δ = 7.28 – 7.20 (m, 3H), 7.13 (dd, J = 7.5, 1.7 Hz, 2H), 4.99 (dd, J = 13.0, 8.1 Hz, 1H), 4.71 (dd, J = 13.0, 7.0 Hz, 1H), 4.05 (dd, J = 6.6, 3.6 Hz, 2H), 3.96 (td, J = 7.4, 4.4 Hz, 1H), 3.70 (d, J = 2.7 Hz, 1H), 1.45 (bs, 2H), 1.17 (t, J = 7.1 Hz, 3H).

13

C-NMR (126 MHz, CDCl3) δ = 173.5, 135.0,

128.9, 128.44 (two signals in the HSQC spectra), 77.0, 61.6, 55.9, 46.4, 14.3. [α]24D = +11.5 (c 1.00, CHCl3), >99% ee. HPLC: Daicel Chiralpak IB, iso-propanol/hexane 10/90, flow rate = 1.0 ml/min, tr: 14.2 min (2S,3R) and 16.8 min (2R,3S), 210 nm. Anal. Calcd. For C12H16N2O4: C, 57.1; H, 6.4; N, 11.1; Found: C, 56.9; H, 6.2; N, 10.8. (2S,3S)-Ethyl 2-amino-4-nitro-3-phenylbutanoate (anti-4g). The title compound was obtained as a white solid (94 mg, 0.37 mmol, 83%). M. p.: 46-47 ºC. IR (neat) 3370, 3285, 1724, 1541, 1374 cm-1. 1

H-NMR (500 MHz, CDCl3) δ = 7.27 – 7.14 (m, 5H), 5.01 (dd, J = 13.0, 4.7 Hz, 1H), 4.70 (dd, J =

12.8, 9.3 Hz, 1H), 3.92 (dd, J = 13.7, 6.8 Hz, 2H), 3.74 (dd, J = 13.8, 7.4 Hz, 1H), 3.62 (bs, 1H), 1.70 (bs, 2H), 0.97 (t, J = 6.9 Hz, 3H). 13C-NMR (126 MHz, CDCl3) δ = 173.3, 136.1, 128.6, 127.9, 127.8, 77.0, 60.9, 57.5, 47.6, 13.5. [α]26D = +6.3 (c 1.00, CHCl3), 93% ee. HPLC: Daicel Chiralpak IC, isopropanol/hexane 10/90, flow rate = 1.0 ml/min, tr: 39.2 min (2S,3S) and 46.7 min (2R,3R), 210 nm. Anal. Calcd. For C12H16N2O4: C, 57.1; H, 6.4; N, 11.1; Found: C, 57.1; H, 6.4; N, 11.1. (2S,3R)-tert-Butyl 2-amino-4-nitro-3-phenylbutanoate (syn-4h). The title compound was obtained as a pale yellow oil (73 mg, 0.26 mmol, 58%). IR (neat) 3392, 3322, 1726, 1548, 1368 cm-1. 1H-NMR (500 MHz, CDCl3) δ = 7.29 – 7.12 (m, 5H), 4.96 (dd, J = 12.8, 8.0 Hz, 1H), 4.69 (dd, J = 12.8, 7.2 Hz, 1H), 3.91 (td, J = 7.5, 4.5 Hz, 1H), 3.60 (d, J = 4.2 Hz, 1H), 1.47 (bs, 2H), 1.31 (s, 9H). 13C-NMR (126 MHz, CDCl3) δ = 172.4, 135.3, 128.8, 128.7, 128.3, 82.2, 77.4, 56.1, 46.4, 28.1. [α]26D = +19.0 (c 1.00, CHCl3), >99% ee. HPLC: Daicel Chiralpak IB, iso-propanol/hexane 10/90, flow rate = 1.0 ml/min, tr: 9.5 min (2S,3R) and 10.7 min (2R,3S), 210 nm. Anal. Calcd. For C14H20N2O4: C, 60.0; H, 7.2; N, 10.0; Found: C, 60.2; H, 7.1; N, 10.1. 30 ACS Paragon Plus Environment

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(2S,3S)-tert-Butyl 2-amino-4-nitro-3-phenylbutanoate (anti-4h). The title compound was obtained as a white solid Yield = 68% (86 mg, 0.31 mmol, 68%). M. p.: 84-86 ºC. IR (neat) 3383, 3314, 1713, 1541, 1382 cm-1. 1H-NMR (500 MHz, CDCl3) δ = 7.30 – 7.10 (m, 5H), 5.00 (dd, J = 12.9, 4.9 Hz, 1H), 4.65 (dd, J = 12.6, 9.5 Hz, 1H), 3.60 (dd, J = 26.2, 17.9 Hz, 1H), 3.49 (d, J = 8.1 Hz, 1H), 1.57 (bs, 2H), 1.15 (s, 9H). 13C-NMR (126 MHz, CDCl3) δ = 173.0, 136.6, 128.7, 128.4, 128.1, 81.8, 78.0, 58.1, 48.3, 27.6. [α]20D = +8.6 (c 1.15, CHCl3), 98% ee. HPLC: Daicel Chiralpak IC, iso-propanol/hexane 10/90, flow rate = 1.0 ml/min, tr: 22.8 min (2S,3S) and 25.9 min (2R,3R), 210 nm. Anal. Calcd. For C14H20N2O4: C, 60.0; H, 7.2; N, 10.0; Found: C, 60.1; H, 7.2; N, 10.0. General method for the synthesis of iminoesters syn-4´b and anti-4´e: A solution of the corresponding α-iminoester 1b (124 mg, 0.60 mmol) or 1e (116 mg, 0.45 mmol), chiral ligand 9 (3.1 mg, 4.95 µmol) and Cu(CH3CN)4PF6 (1.7 mg, 4.50 µmol) in 2.0 ml of dry THF was stirred at at -60 ºC for one hour. Then, a precooled (-60 ºC) solution of nitroalkene 2a (89 mg 0.60 mmol in the case of 1b, and 68 mg 0.46 mmol for 1e) in 1.0 ml of dry THF and triethylamine (3.2 µl, 0.023 mmol) were successively added. The resulting mixture was stirred at -60ºC for 12 h and then it was filtered through a pad of celite. Rotary evaporation of the solvent gave an oily residue, which was purified by flash chromatography on silica gel (EtOAc:n-hexane 1:4). (2S,3R)-Methyl 2-(((E)-4-methoxybenzylidene)amino)-4-nitro-3-phenylbutanoate (syn-4´b). The title compound was obtained as a yellow oil (207 mg, 0.58 mmol, 97%). IR (neat): 3022, 2953, 1735, 1547, 1208, 701. 1H-NMR (500 MHz, CDCl3) δ = 7.33 (s, 1H), 7.32 - 7.36 (d, J = 8.6 Hz, 2H), 7.19 7.21 (d, J = 7.0 Hz, 2H), 7.36 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 7.3 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 5.10 (dd, J = 13.1, 8.2 Hz, 1H), 4.80 (dd, J = 13.1, 6.7 Hz, 1H), 4.05 – 4.08 (m, 1H), 3.82 - 3.84 (m, 1H), 3.71 (s, 6H).13C-NMR (126 MHz, CDCl3) δ 173.9, 134.8, 129.2, 128.9, 128.8, 128.4, 128.2, 128.1, 128.0, 127.8, 127.3, 76.7, 55.8, 52.3, 46.2. Anal. Calcd. For C19H20N2O5: C, 64.0; H, 5.7; N, 7.9; Found:



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C, 63.9; H, 5.7; N, 7.9. HRMS [M+H]+ calcd. for C19H21N2O5: 357.1450; found: 357.1457. [α]21D = 115 (c 0.4, CHCl3). (2S,3R)Methyl -2-((diphenylmethylene)amino)-4-nitro-3-phenylbutanoate (anti-4´e). The title compound was obtained as a yellow oil (169 mg, 0.42 mmol, 95%) . 1H-NMR (400 MHz, CDCl3) δ= 7.60 (d, J = 6.2 Hz, 2H), 7.30 - 7.45 (m, 4H), 7.14 – 7.22 (m, 10H), 6.61 (m, 2H), 5.14-5.23 (m, J = 9.4 Hz, 2H), 4.33 - 4.40 (m, J = 9.5, 4.6 Hz, 1H), 4.33 (d, J = 4.1 Hz, 1H), 3.71 (s, 3H).

13

C-NMR (101

MHz, CDCl3) δ 171.8, 171.0, 139.0, 137.1, 135.8, 132.3, 129.0, 128.8, 128.8, 128.7, 128.6, 128.0, 127.5, 75.9, 68.5, 55.5, 51.9. [α]21D = -137 (c 0.4, CHCl3). Lit.:23 [α]23D = -139 (c 0.4, CHCl3). Synthesis of pyrrolidines exo-3b and endo-3b. Method A : A solution of α-iminoester 1b (124 mg, 0.60 mmol), chiral ligand 9 (3.1 mg, 4.95 µmol) and Cu(CH3CN)4PF6 (1.7 mg, 4.50 µmol) in 2.0 ml of dry THF was stirred at at -60 ºC for one hour. Then, a precooled (-60 ºC) solution of nitroalkene 2a (89 mg 0.60 mmol) in 1.0 ml of dry THF and triethylamine (3.2 µl, 0.023 mmol) were successively added. Then the cooling bath was removed and the reaction mixture was allowed to reach room temperature. Stirring was resumed at room temperature for additional 12 h and then it was filtered through a pad of celite. Rotary evaporation of the solvent gave an oily residue, whose 1H-NMR analysis showed a exo3b: endo-3b ratio of 80:20. Both diastereomers were separated purified by flash chromatography on silica gel (EtOAc:n-hexane 1:4). Method B: The procedure was similar to that indicated in Method A, but the addition of the reactants and catalysts as well as the whole reaction were conducted at room temperature for 12 h. 1H-NMR analysis of the reaction mixture showed a exo-3b: endo-3b ratio of 50:50. (2S,3S,4R,5S)-Methyl 5-(4-methoxyphenyl)-4-nitro-3-phenylpyrrolidine-2-carboxylate (exo-3b). The title compound was obtained as a pale yellow solid (Method B: 40%, (85 mg, 0.24 mmol, 40%). M. p.: 133-134 ºC (lit.:24 135-136 ºC) 1H-NMR (500 MHz, CDCl3) δ = 7.48 (d, J = 8.5, 2H), 7.34 – 7.22 (m, 5H), 6.94 (d, J = 8.5, 2H), 5.19 (t, J = 8.2, 1H), 4.69 (d, J = 8.3, 1H), 4.47 (d, J = 9.1, 1H), 4.38 (t, J 32 ACS Paragon Plus Environment

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= 8.6, 1H), 3.82 (s, 3H), 3.28 (s, 3H), 2.69 (bs, 1H). [α]21D = +81.7 (c 0.4, CHCl3). Lit.:24 [α]20D = +82.8 (c 1.68, CHCl3). (2S,3R,4S,5S)-methyl 5-(4-methoxyphenyl)-4-nitro-3-phenylpyrrolidine-2-carboxylate (endo-3b). The title compound was obtained as a pale yellow solid (Method B: 78 mg, 0.22 mmol, 38%). M. p.: 118-120 ºC (lit.:24 116-118 ºC). 1H-NMR (500 MHz, CDCl3) δ = 7.41 (t, J = 7.4, 2H), 7.37 – 7.27 (m, 5H), 6.89 (d, J = 8.6, 2H), 5.23 (dd, J = 6.4, 3.6, 1H), 4.88 (d, J = 6.5, 1H), 4.22 (dd, J = 7.2, 3.5, 1H), 4.13 (d, J = 7.4, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.28 (bs, 1H). [α]21D = -47.3 (c 0.4, CHCl3). Lit.:24 [α]21D = -51.1 (c 0.4, CHCl3). (2S*,3R*,4S*)-Methyl 4-nitro-3,5,5-triphenyl-pyrrolidine-2-carboxylate (endo-3e). Method A: A solution of α-iminoester 1e (116 mg, 0.45 mmol), chiral ligand 9 (3.1 mg, 4.95 µmol) and Cu(CH3CN)4PF6 (1.7 mg, 4.50 µmol) in 2.0 ml of dry THF was stirred at at -60 ºC for one hour. Then, a precooled (-60 ºC) solution of nitroalkene 2a (68 mg 0.46 mmol) in 1.0 ml of dry THF and triethylamine (3.2 µl, 0.023 mmol) were successively added. The resulting mixture was stirred at -60ºC or at room tempetature for 12 h and then it was refluxed for additional 12 h . Then, it was filtered through a pad of celite. Rotary evaporation of the solvent gave an oily residue, which was purified by by flash chromatography on silica gel (EtOAc:n-hexane 1:4). Method B: The reactants and catalysts were mixed in 3 ml of a 1:3 mixture of THF:toluene in a closed vessel and irradiated with microwaves at 100 ºC for 3 h. After workup similar to that followed in Method A, an oily residue was obtained, which was purified by flash chromatography on silica gel (EtOAc:n-hexane 1:4). The title compound was obtained as a yellow oil (161 mg, 0.40 mmol, 90%). IR (neat): 3059, 2950, 1739, 1210, 1518, 653. 1H-NMR (500 MHz, CDCl3) δ =7.85 – 7.73 (m, 2H), 7.52 – 7.45 (m, 2H), 7.41 (t, J = 7.7 Hz, 2H), 7.29 (dd, J = 5.3, 2.5 Hz, 2H), 7.22 (d, J = 7.2 Hz, 2H), 6.83 – 6.72 (m, 2H), 6.10 (d, J = 4.4 Hz, 1H), 4.16 (dd, J = 8.0, 4.4 Hz, 1H), 4.06 (d, J = 8.3 Hz, 2H), 3.77 (s, 3H).13C-NMR (126 MHz, CDCl3) δ 171.8, 142.2, 141.8, 137.3, 129.2, 128.9, 128.8, 128.6, 128.4, 128.3, 128.2, 128.0, 127.9, 127.8, 127.8, 127.3, 126.7, 125.4, 33 ACS Paragon Plus Environment


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101.5, 77.4, 77.3, 77.1, 76.8, 65.4, 58.4, 52.6. Anal. Calcd. For C24H22N2O4: C, 71.6; H, 5.5; N, 7.0; Found: C, 71.4; H, 5.6; N, 7.0. HRMS [M+H]+ calcd. for C24H23N2O4: 403.1658; found: 403.1664. General procedure for the synthesis of α-aminolactams trans and cis-6a-c. A solution of the corresponding adduct syn- or anti-4a-c (1.6 mmol) in MeOH (160 ml, 0.01 M) was filtered through a filter with a pore size of 0.20 µm. The resulting solution was passed through H-Cube® hydrogenator flow reactor provided with a Ni-Raney cartridge at 65 ºC, 10 bar of hydrogen pressure and a flow rate of 1.0 ml/min. The recovered solution was concentrated under reduced pressure to afford the corresponding pure α-aminolactam trans or cis-6a-c. (3S,4R)-3-Amino-4-phenylpyrrolidin-2-one (trans-6a). The title compound was obtained from syn-4a as a white solid (282 mg, 1.6 mmol, ca.100%). M. p.: 101-103 ºC. IR (neat) 3361, 3327, 3267, 3159, 1712, 1667 cm-1. 1H-NMR (500 MHz, CDCl3) δ = 7.45 – 7.25 (m, 5H), 6.06 (bs, 1H), 3.71 – 3.65 (m, 2H), 3.43 (t, J = 9.7 Hz, 1H), 3.33 (dd, J = 18.5, 9.9 Hz, 1H), 1.68 (bs, 2H).

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C-NMR (126 MHz,

CDCl3) δ = 178.1, 139.3, 129.1, 127.7, 127.6, 58.9, 51.2, 45.9. [α]26D = -84.8 (c 1.00, CHCl3). Anal. Calc. For C10H12N2O: C, 68.2; H, 6.9; N, 15.9; Found: C, 68.6; H, 6.8; N, 15.9. (3S,4S)-3-Amino-4-phenylpyrrolidin-2-one (cis-6a). The title compound was obtained from anti-4 as a white solid. (282 mg, 1.6 mmol, ca. 100%). M. p.: 140-141 ºC. IR (neat) 3369, 3307, 3166, 3091, 1710, 1681 cm-1. 1H-NMR (500 MHz, CDCl3) δ = 7.41 – 7.18 (m, 5H), 6.12 (bs, 1H), 3.84 – 3.74 (m, 3H), 3.62 (d, J = 9.0 Hz, 1H), 1.15 (bs, 2H).

13

C-NMR (126 MHz, CDCl3) δ = 178.5, 138.2, 129.0, 128.2,

127.7, 55.5, 45.6, 45.1. [α]26D = -47.2 (c 1.00, CHCl3). Anal. Calc. For C10H12N2O: C, 68.2; H, 6.9; N, 15.9; Found: C, 68.2; H, 7.4; N, 16.0. (3S,4R)-3-amino-4-(4-fluorophenyl)pyrrolidin-2-one (trans-6b). The title compound was obtained from syn-4b as a white solid (311 mg, 1.6 mmol, ca. 100%). M. p.: 115-118 ºC. IR (neat) 3217, 3081, 1686, 1602, 1589, 1160 cm-1H-NMR (500 MHz, CDCl3) δ = 7.35 – 7.29 (m, 2H), 7.08 (t, J = 8.3 Hz, 2H), 6.45 (bs, 1H), 3.68 – 3.62 (m, 2H), 3.40-3.31 (m, 2H), 1.97 (bs, 2H). 13C-NMR (126 MHz, CDCl3) 34 ACS Paragon Plus Environment

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δ =177.3, 163.1, 161.2, 134.7, 129.0, 115.8, 58.7, 50.1, 45.7. 19F-NMR(375 MHz, CDCl3) δ = -114.92. [α]26D = -27 (c 1.00, CHCl3). Anal. Calc. For C10H11FN2O: C, 61.8; H, 5.7; N, 14.4; Found: C, 61.8; H, 5.7 N, 14.3. (3S,4S)-3-amino-4-(4-fluorophenyl)pyrrolidin-2-one (cis-6b). The title compound was obtained from anti-4b as a white solid (311 mg, 1.6 mmol, ca. 100%). M. p.: 137-141 ºC. IR(neat) 3221, 3057, 1676, 1612, 1579, 1140cm-1. 1H-NMR (500 MHz, CDCl3) δ= 7.39 - 7.29 (m, 2H), 6.61 (bs, 1H), 3.83-376 (m, 2H), 3.64 - 3.61 (m, 1H), 1.65 (bs, 2H).

13

C-NMR (126 MHz, CDCl3) δ = 178.1, 163.3, 160.9, 133.8,

129.6, 129.6, 115.8, 115.6, 45.6, 44.3, 30.3, 29.6. 19F-NMR (375 MHz, CDCl3) δ = -114.75. [α]26D = 10 (c 0.5, CHCl3). Anal. Calc. For C10H11FN2O: C, 61.8; H, 5.7; N, 14.4; Found: C, 61.9; H, 5.6 N, 14.3. (3S,4R)-3-amino-4-(4-methoxyphenyl)pyrrolidin-2-one (trans-6c). The title compound was obtained from syn-4c as a white solid (330 mg, 1.6 mmol, ca. 100%). M. p.: 110-112 ºC. IR (neat) 3207, 3151, 1701, 1610, 1513, 1248 cm-1. 1H-NMR (500 MHz, CDCl3) δ = 7.22 (d, J = 8.3 Hz, 2H), 6.92 (dd, J = 15.5, 8.1 Hz, 2H), 5.93 (s, 1H), 3.83 (d, J = 4.6 Hz, 3H), 3.77 (d, J = 8.3 Hz, 1H), 3.60 (dd, J = 20.0, 10.8 Hz, 1H), 3.39 (t, J = 9.7 Hz, 1H), 3.27 (d, J = 9.3 Hz, 1H), 1.68 (bs, 2H).13C-NMR (126 MHz, CDCl3) δ = 177.3, 158.8, 130.7, 128.4(2C), 114.1(2C), 58.5, 55.1, 49.6, 45.98. [α]26D = -80 (c 1.00, CHCl3). Anal. Calc. For C11H14N2O2: C, 64.1; H, 6.8; N, 13.6; Found: C, 63.9.; H, 6.7; N, 13.5. (3S,4S)-3-amino-4-(4-methoxyphenyl)pyrrolidin-2-one (cis-6c). The title compound was obtained from anti-4c as a white solid (330 mg, 1.6 mmol, ca. 100%). M. p.: 142-144 ºC. IR (neat) 3242, 3186, 2285, 1704, 1720, 1586 cm-1. 1H-NMR (500 MHz, CDCl3) δ = 7.21 (d, J = 8.1 Hz, 2H), 6.89 (d, J = 8.3 Hz, 2H), 3.81 (s, 3H), 3.77 (d, J = 7.7 Hz, 1H), 3.57 (d, J = 9.8 Hz, 1H), 1.57 (s, 2H). 13C-NMR (126 MHz, CDCl3) δ = 177.3, 158.9, 130.7, 128.4(2C), 114.2(2C), 58.6, 55.2, 49.7, 45.8. [α]26D = +13.6 (c 1.00, CHCl3). Anal. Calc. For C11H14N2O2: C, 64.1; H, 6.8; N, 13.6; Found: C, 63.9.; H, 6.8; N, 13.3.



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General procedure for the preparation of α-iminolactams cis and trans-10a-e. To a solution of αamino−γ−lactam trans- or cis-6a-c (1.0 mmol) in dry CH2Cl2 (3 ml), the corresponding aldehyde 8a-c (1.0 mmol) and MgSO4 was added at room temperature. The resulting mixture was stirred at the same temperature for 18 hours and then the solid was filtered off. The solvent was evaporated under reduced pressure to afford the pure product, which was used in the next step without further purification. General procedure for the synthesis of 1,7-diazaspiro[4.4]nonan-6-ones 5a-i and ent-5a-i, via (3+2) cycloadditions between α-iminolactams trans- or cis-10a-e and π-deficient alkenes. A solution of αimino−γ−lactam 10a-e (0.6 mmol), the corresponding dipolarophile (0.6 mmol), AgOAc (0.9 mmol) and Et3N (0.9 mmol) in 5 ml of toluene was stirred at room temperature in the absence of light. The reaction was monitored by TLC and once the starting material was consumed the mixture was filtered through a pad of celite or silica gel. The filtrate was concentrated under reduced pressure and the residue was purified by trituration with Et2O or by flash chromatography on silica gel (EtOAc:n-hexane 1:3) to afford the corresponding pure product. (2S,3S,4S,5R,9R)-2,9-diphenyl-3,4-bis(phenylsulfonyl)-1,7-diazaspiro[4.4]nonan-6-one (5a). The title compound was obtained from trans-10a and 7a as a white pale solid (292 mg, 0.51 mmol, 85%). M. p. 231-233 ºC. IR (neat) 3321, 3064, 1718, 1147 746 cm-1. 1H-NMR (500 MHz, CDCl3) δ = 8.07 (d, J = 7.7 Hz, 2H), 7.78 (t, J = 7.5 Hz, 2H), 7.68 (t, J = 7.6 Hz, 2H), 7.55 (d, J = 7.7 Hz, 2H), 7.49 (t, J = 7.5 Hz, 2H), 7.43 (d, J = 7.5 Hz, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.31 – 7.26 (m, 2H), 7.06 (dt, J = 14.6, 6.6 Hz, 2H), 7.01 (d, J = 7.2 Hz, 2H), 6.36 (s, 1H), 4.49 (d, J = 3.2 Hz, 1H), 4.29 (d, J = 3.2 Hz, 1H), 4.11 (d, J = 5.8 Hz, 1H), 3.88 (dd, J = 10.8, 5.9 Hz, 1H), 3.50 (d, J = 10.6 Hz, 1H), 2.93 (d, J = 9.1 Hz, 1H), 1.63 (bs, 1H).

13

C-NMR (126 MHz, CDCl3) δ 172.0, 138.7, 138.0, 137.5, 137.4, 134.6, 134.2, 129.6,

129.4, 129.2, 128.7, 128.5, 128.3, 128.2, 127.93, 127.8, 127.4, 73.6, 72.4, 71.7, 64.17 51.6, 45.4. [α]26D = -63.8 (c 0.5, CHCl3). Anal. Calcd. For C31H28N2O5S2: C, 65.0; H, 4.9; N, 4.9; Found: C, 64.9; H, 4.9; N, 5.1. 36 ACS Paragon Plus Environment

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(3S,3'R,3a'S,4R,6a'R)-5'-methyl-3',4-diphenyldihydro-2'H-spiro[pyrrolidine-3,1'-pyrrolo[3,4c]pyrrole]-2,4',6'(5'H,6a'H)-trione (5b). The title compound was obtained from trans-10a and 7b as a white solid (198 mg, 0.53 mmol, 88%). M. p.: 237-238 ºC. IR (neat) 3333 (broad signal), 1773, 1689 (broad signal), 1433 cm-1. 1H-NMR (500 MHz, CDCl3) δ = 7.36 – 7.20 (m, 10H), 6.93 (s, 1H), 4.33 (dd, J = 7.8, 5.3 Hz, 1H), 4.06 (dd, J = 10.7, 6.5 Hz, 1H), 3.64 – 3.57 (m, 2H), 3.53 (t, J = 7.9 Hz, 1H), 3.43 (d, J = 7.7 Hz, 1H), 2.91 (s, 3H), 2.12 (d, J = 5.1 Hz, 1H).

13

C-NMR (126 MHz, CDCl3) δ = 175.2,

174.6, 174.5, 138.1, 136.8, 129.3, 128.2, 128.1, 128.1, 127.6, 127.1, 71.8, 62.7, 53.4, 51.5, 49.7, 45.3, 25.1. [α]26D = +40.5 (c 1.00, CHCl3). Anal. Calcd. For C22H21N3O3: C, 70.4; H, 5.6; N, 11.2; Found: C, 70.3;

H,

6.0;

N,

11.5.

(3R,3'S,3a'R,4S,6a'S)-5'-methyl-3',4

diphenyltetrahydro-4'H-

spiro[pyrrolidine-3,1'-pyrrolo[3,4-c]pyrrole]-2,4',6'(5'H)-trione (ent-5b): The title compound was obtained from cis-10a and 7b as a white solid (192 mg, 0.51 mmol, 85%). [α]26D = -36.3 (c 1.00, CHCl3). (2S,3S,4S,5S,9R)-3-nitro-2,4,9-triphenyl-1,7-diazaspiro[4.4]nonan-6-one (5c). The title compound was obtained from trans-10a and 2a as a white solid (176 mg, 0.43 mmol, 71%). M. p.: 231-232 ºC. IR (neat) 3381, 3355, 3197, 1726, 1699, 1549, 1366 cm-1. 1H-NMR (500 MHz, CDCl3) δ = 7.42 – 7.21 (m, 15H), 6.05 (s, 1H), 5.53 (dd, J = 11.3, 9.6 Hz, 1H), 4.87 (d, J = 11.4 Hz, 1H), 4.31 (dd, J = 9.1, 7.4 Hz, 1H), 3.32 – 3.24 (m, 2H), 2.83 (t, J = 7.7 Hz, 1H), 2.51 (d, J = 7.1 Hz, 1H).

13

C-NMR (126 MHz,

CDCl3) δ = 176.2, 138.2, 137.2, 133.6, 129.2, 129.0, 128.8, 128.5, 128.4, 128.1, 127.8, 127.6, 90.9, 72.5, 62.9, 53.9, 46.2, 45.5. [α]26D = -85.2 (c 1.00, CHCl3). Anal. Calcd. For C25H23N3O3: C, 72.6; H, 5.6; N, 10.2; Found: C, 72.6; H, 5.9; N, 10.3. (2R,3R,4R,5R,9S)-3-nitro-2,4,9-triphenyl-1,7diazaspiro[4.4]nonan-6-one (ent-5c). The title compound was obtained from cis-10a and 2a as a white solid (186 mg, 0.45 mmol, 75%). [α]26D = +84.3 (c 1.00, CHCl3). (2S,3S,4S,5S,9R)-9-(4-methoxyphenyl)-3-nitro-2,4-diphenyl-1,7 diazaspiro[4.4]nonan-6-one (5d). The title compound was obtained from trans-10b and 2a as a white solid (162 mg, 0.37 mmol, 61%). M. p.: 240-241 ºC. IR (neat) 3259, 3407, 1703, 1547, 1509, 1228, 858, cm-1. 1H-NMR (500 MHz, CDCl3) δ 37 ACS Paragon Plus Environment


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= 7.44 (dd, J = 7.4, 1.8 Hz, 2H), 7.39 (d, J = 1.5 Hz, 2H), 7.37 – 7.35 (m, 4H), 7.34 – 7.29 (m, 2H), 6.94 (d, J = 8.6 Hz, 2H), 5.93 (s, 1H), 5.54 (dd, J = 11.5, 9.4 Hz, 1H), 4.93 (d, J = 11.3 Hz, 1H), 4.43 – 4.34 (m, 1H), 3.87 (s, 3H), 3.80 (d, J = 8.4 Hz, 1H), 3.32 (dd, J = 9.5, 6.7 Hz, 1H), 3.29 – 3.21 (m, 1H), 3.00 – 2.88 (m, 1H), 2.56 (bs, 1H).13C-NMR (126 MHz, CDCl3) δ = 175.9, 137.3, 133.8, 130.1, 129.2, 128.9, 128.6, 128.3, 127.9, 127.6, 114.4, 91.2, 63.2, 55.3, 53.7, 46.3, 44.7. [α]26D = -60.5 (c 1.00, CHCl3). Anal. Calcd. For C26H25N3O4: C, 70.4; H, 5.7; N, 9.5; Found: C, 70.3; H, 5.6; N, 9.6. (2R,3R,4R,5R,9R)9-(4-methoxyphenyl)-3-nitro-2,4-diphenyl-1,7-diazaspiro[4.4]nonan-6-one (ent-5d). The title compound was obtained from cis-10b and 2a as a white solid (165 mg, 0.37 mmol, 62%). [α]26D = +61.2 (c 1.00, CHCl3). (2R,3R,4R,5R,9S)-9-(4-fluorophenyl)-3-nitro-2,4-diphenyl-1,7-diazaspiro[4.4]nonan-6-one

(5e).

The title compound was obtained from trans-10c and 2a as a white solid (132 mg, 0.31 mmol, 51%). M. p.: 219-223 ºC. IR (neat) 3398, 1739, 1508, 1292, 1164, 749 cm-1. 1H-NMR (500 MHz, CDCl3) δ = 7.58 – 7.24 (m, 7H), 7.10 (t, J = 8.3 Hz, 1H), 6.22 (s, 1H), 5.53 (dd, J = 11.3, 9.1 Hz, 1H), 4.93 (d, J = 11.2 Hz, 1H), 4.35 (t, J = 8.1 Hz, 1H), 3.30 (dq, J = 13.8, 7.0 Hz, 1H), 2.95 (t, J = 8.0 Hz, 1H), 2.62 (d, J = 7.2 Hz, 1H). 13C-NMR (126 MHz, CDCl3) δ = 175.85, 162.4 (d, J1C-F = 245.7 Hz), 136.9, 133.6 (d, J3C-F = 3.23 Hz), 130.7, 130.7, 129.3, 129.1, 128.9, 128.6, 128.5, 128.4, 127.8, 127.6, 127.5, 116.0, 115.8, 91.1, 63.5, 54.0, 46.5, 44.8.

19

F-NMR (375 MHz, CDCl3) δ = -110.95. [α]26D = -40.2 (c 1.00,

CHCl3). Anal. Calcd. For C25H22FN3O3: C, 69.5; H, 5.1; N, 9.7; Found: C, 69.5; H, 5.3; N, 9.8. (2S,3S,4S,5S,9R)-9-(4-fluorophenyl)-3-nitro-2,4-diphenyl-1,7-diazaspiro[4.4]nonan-6-one (ent-5e). The title compound was obtained from cis-10c and 2a as a white solid (150 mg, 0.35 mmol, 58%). [α]26D = +68.2 (c 1.00, CHCl3). (2S,3S,4S,5S,9R)-2-(4-methoxyphenyl)-3-nitro-4,9-diphenyl-1,7-diazaspiro[4.4]nonan-6-one

(5f).

The title compound was obtained from trans-10d and 2a as a white solid (181 mg, 0.41 mmol, 68%). M. p.: 246-247 ºC. IR (neat) 3273, 3012, 1703, 1549, 1512, 1246, 1030 cm-1. 1H-NMR (500 MHz, CDCl3) δ = 7.44 (d, J = 7.8 Hz, 2H), 7.42 – 7.37 (m, 6H), 7.35 (s, 2H), 7.29 (d, J = 2.2 Hz, 2H), 6.94 – 6.72 (m, 38 ACS Paragon Plus Environment

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2H), 6.30 (bs, 1H), 5.61 – 5.45 (m, 1H), 4.91 (d, J = 11.6 Hz, 1H), 4.41 – 4.28 (m, 1H), 3.78 (d, J = 2.1 Hz, 3H), 3.33 (dd, J = 15.7, 8.0 Hz, 1H), 2.89 (t, J = 8.5 Hz, 1H), 2.49 (d, J = 9.1 Hz, 1H), 1.61 (bs, 1H).

13

C-NMR (126 MHz, CDCl3) δ = 176.1, 159.9, 138.1, 133.7, 129.2, 129.0, 129.0, 128.8, 128.1,

127.9, 113.95, 90.9, 72.4, 62.6, 55.2, 53.7, 46.2, 45.5. [α]26D = -65.1 (c 1.00, CHCl3). Calcd. For C26H25N3O4: C, 70.4; H, 5.7; N, 9.5; Found: C, 70.2; H, 5.9; N, 9.9. (2R,3R,4R,5R,9S)-2-(4methoxyphenyl)-3-nitro-4,9-diphenyl-1,7-diazaspiro[4.4]nonan-6-one (ent-5f). The title compound was obtained from cis-10d and 2a as a white solid (189 mg, 0.43 mmol, 71%). [α]26D = +60.5 (c 1.00, CHCl3). (2S,3S,4S,5S,9R)-2-(4-fluorophenyl)-3-nitro-4,9-diphenyl-1,7-diazaspiro[4.4]nonan-6-one (5g). The title compound was obtained from trans-10e and 2a as a pale brown solid (181 mg, 0.42 mmol). M. p.: 246-247 ºC. IR (neat) 3390, 1751, 1510, 1275, 1174, 751 cm-1. 1H-NMR (500 MHz, CDCl3) δ = 7.50 7.46 (m, 4H), 7.37 - 7.40 (m, J = 7.6 Hz, 6H), 7.35 - 7.33 (m, 2H), 7.00 - 6.97 (m, 2H), 6.52 (bs, 1H), 5.61 (t, J = 10.5 Hz, 1H), 4.87 (d, J = 11.6 Hz, 1H), 4.41 (d, J = 9.4 Hz, 1H), 3.33 (d, J = 6.3 Hz, 2H), 2.92 – 2.75 (m, 1H), 2.46 (s, 1H), 1.71 – 1.50 (m, 1H). 13C-NMR (126 MHz, CDCl3) δ = 176.0, 162.9 (d, J1C-F=247.8 Hz), 138.1, 133.1(d, J3C-F=3.23 Hz), 129.4, 129.3, 129.1, 128.6, 128.4, 128.1, 127.7, 115.4 (d, J2C-F=21.63 Hz), 90.3, 72.1, 61.8, 53.3, 45.9, 45.5, 41.3, 31.5, 22.6, 14.1. 19F-NMR (376 MHz, CDCl3) δ = -112.93. [α]26D = -21.0 (c 1.00, CHCl3). Anal. Calcd. For C25H22FN3O3: C, 69.5; H, 5.1; N, 9.7; Found: C, 69.7; H, 5.0; N, 9.5. (2R,3R,4R,5R,9S)-2-(4-fluorophenyl)-3-nitro-4,9-diphenyl-1,7diazaspiro[4.4]nonan-6-one (ent-5g). The title compound was obtained from cis-10e and 2a as a pale brown solid (145 mg, 0.34 mmol, 56%). [α]26D = +20.6 (c 1.00, CHCl3). (2R,3S,5R,9R)-3-methoxycarbonyl-2,9-diphenyl-1,7-diazaspiro[4.4]nonan-6-one (5h). The title compound was obtained from trans-10a and 7c as a white solid (179 mg, 0.51 mmol, 85%). M. p.: 210-211 ºC. IR (neat) 3465 (broad signal), 1725, 1697 cm-1. 1H-NMR (500 MHz, CDCl3) δ = 7.32 – 7.06 (m, 11H), 4.09 (d, J = 9.4 Hz, 1H), 3.66 (dd, J = 9.8, 7.4 Hz, 1H), 3.54 (dd, J = 10.0, 4.1 Hz, 1H), 3.27 (dd, J = 6.6, 4.5 Hz, 1H), 3.22 (ddd, J = 10.7, 9.6, 7.5 Hz, 1H), 3.10 (s, 3H), 2.75 (t, J = 12.0 Hz, 1H), 2.14 39 ACS Paragon Plus Environment


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(bs, 1H), 2.05 (dd, J = 12.6, 7.1 Hz, 1H). 13C-NMR (126 MHz, CDCl3) δ = 178.5, 171.8, 141.1, 139.1, 128.8, 128.2, 127.9, 127.6, 127.4, 127.4, 70.2, 63.8, 51.8, 51.2, 49.8, 45.5, 36.8. [α]26D = -10.5 (c 1.00, CHCl3). Anal. Calcd. For C21H22N2O3: C, 72.0; H, 6.3; N, 8.0; Found: C, 72.1; H, 5.9; N, 8.2. (2R,3S,5R,9R)-tert-Butyl-6-oxo-2,9-diphenyl-1,7-diazaspiro[4.4]nonane-3-carboxylate (5i). The title compound was obtained from trans-10a and 7d as a white solid (177 mg, 0.45 mmol, 75%). M. p.: 223225 ºC. IR (neat) 3222 (broad signal), 2975, 2919, 1701, 1151, 698 cm1. 1H-NMR (500 MHz, CDCl3) δ = 7.47 – 7.14 (m, 10H), 6.42 (s, 1H), 4.13 (d, J = 9.4 Hz, 1H), 3.75 (dd, J = 10.0, 7.0 Hz, 1H), 3.62 (t, J = 5.1 Hz, 1H), 3.36 (dd, J = 7.1, 4.3 Hz, 1H), 3.24 (td, J = 10.2, 9.7, 7.3 Hz, 1H), 2.81 (t, J = 12.1 Hz, 1H), 2.16 (dd, J =12.8, 7.2 Hz, 1H), 1.03 (s, 9H). 13C-NMR (126 MHz, CDCl3) δ = 178.2, 170.5, 141.7, 139.3, 129.0, 128.8, 128.2, 128.1, 128.0, 127.6, 127.4, 127.36, 80.5, 69.9, 63.9, 52.0, 50.7, 45.6, 45.5, 37.6, 27.5. [α]26D = -8.5 (c 1.00, CHCl3). Anal. Calcd. For C24H28N2O3: C, 73.4; H, 7.2; N, 7.1; Found: C, 73.0; H, 7.4; N, 7.5. (2S,3R,5S,9S)-tert-butyl-6-oxo-2,9-diphenyl-1,7-diazaspiro[4.4]nonane-3carboxylate (ent-5i). The title compound was obtained from cis-10a and 7d as a white solid (170 mg, 0.43 mmol, 72%). [α]26D = +10.7 (c 1.00, CHCl3). General procedure for the synthesis of spiro acids 11 and ent-11. Spiro tert-butyl ester 5i or ent-5i (392 mg, 1.0 mmol) was allowed to react with TFA (8 mL) in CH2Cl2 (15 mL) overnight at room temperature. Rotary evaporation of the reaction mixture under reduced pressure yielded a residue, which was purified by precipitation in EtOAc:n-hexane to afford the desired acid. (2R,3S,5R,9R)-6-oxo-2,9-diphenyl-1,7-diazaspiro[4.4]nonane-3-carboxylic acid. (11). The title compound was obtained from 11 as a white solid (242 mg, 0.72 mmol, 72%). M. p.: 245-247 ºC. 1HNMR (400 MHz, DMSO-d6) δ = 11.88 (bs, 1H), 8.18 (s, 1H), 7.42 (d, J = 7.3 Hz, 2H), 7.38 – 7.25 (m, 5H), 7.24 – 7.12 (m, 3H), 3.94 (d, J = 9.1 Hz, 1H), 3.54 – 3.47 (m, 1H), 3.47 – 3.29 (m, 3H), 3.04 (q, J = 9.2 Hz, 1H), 2.45 (d, J = 11.9 Hz, 1H), 2.07 (dd, J = 12.6, 7.2, 1H). 13C-NMR (126 MHz, DMSO-d6) δ = 177.7, 173.0, 142.7, 140.1, 129.1, 128.7, 128.0, 127.3, 69.9, 63.5, 51.4, 49.8, 44.8, 36.5. [α]26D = 40 ACS Paragon Plus Environment

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+40.5 (c 1.00, CHCl3). Anal. Calcd. For C22H21N3O3: C, 70.4; H, 5.6; N, 11.2; Found: C, 70.3; H, 6.0; N, 11.5. (2S,3R,5S,9S)-6-oxo-2,9-diphenyl-1,7-diazaspiro[4.4]nonane-3-carboxylic acid. (ent-11). Yield = 68% (229 mg, 0.68 mmol). White solid, [α]26D = -37.1 (c 1.00, CHCl3). General procedure for the synthesis of hydroxamic acids 14 and ent-14. A mixture of spiro acid 11 or ent-11 (336 mg, 1.0 mmol), methyl-4-(aminomethyl)benzoate hydrochloride 12 (202 mg, 1.0 mmol) and O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (353 mg, 1.1 mmol) in dry DMF (1.8 ml) was cooled to 0ºC under argon atmosphere. Then, a mixture of Et3N (0.42 mL, 3.0 mmol) and dry DMF (1 mL) was added dropwise, and the resulting mixture was stirred for 1.5 h at 0ºC. Then, EtOAc was added, and the organic layer washed five times with water, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford the corresponding methyl ester 13 or ent-13, which was used in the next step without further purification. To a solution of hydroxylamine hydrochloride (261 mg, 3.75 mmol) and phenolphthalein (1 mg) in methanol (1.25 mL) at 0ºC and under argon atmosphere a precooled 4M solution of NaOMe in methanol was added dropwise until permanent pink color was observed. Then, the corresponding methyl ester 13 or ent-13 (604 mg, 1.25 mmol) was added, followed by 1.4 mL of the same precooled 4M solution of NaOMe in methanol. The resulting mixture was stirred for 26 h at room temperature. During the course of the reaction a precipitate was observed. Then, water was added (3 mL) and the solution was acidified with glacial acetic acid to pH 2. The organic layer was separated and extracted three times with CH2Cl2, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford the pure product 14 or ent-14, which was purified by trituration in EtOAc:n-hexane. (2R,3S,5R,9R)-N-(4-(hydroxycarbamoyl)benzyl)-6-oxo-2,9-diphenyl-1,7-diazaspiro[4.4]nonane-3carboxamide (14). The title compounds was obtained from 13 as a pale red solid (594 mg, 1.23 mmol, 98%). M. p. 50-51 ºC. 1H-NMR (500 MHz, DMSO-d6) δ = 8.51 (t, J = 5.6 Hz, 1H), 8.25 (bs, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 7.2 Hz, 2H), 7.32 (t, J = 7.3 Hz, 2H), 41 ACS Paragon Plus Environment


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7.28 - 7.25 (m, 1H), 7.19 - 7.12 (m, 5H) 7.03 (t, J = 7.0 Hz, 1H), 6.93 (d, J = 7.8 Hz, 2H), 6.84 (d, J = 7.7 Hz, 1H), 4.00 – 3.91 (m, 1H), 3.80 – 3.66 (m, 1H), 3.52 (m, 2H), 3.44 (d, J = 6.4 Hz, 1H), 3.01 (m, 1H), 2.70 (s, 1H), 2.19 (dd, J = 13.3, 7.4 Hz, 1H).

13

C-NMR (126 MHz, DMSO-d6) δ 178.4, 174.3,

171.5, 163.8, 142.8, 141.4, 139.6, 131.8, 129.4, 129.0, 128.8, 128.0, 127.9, 127.5, 127.0, 126.7, 122.4, 121.5, 118.3, 112.5, 69.2, 64.2, 51.8, 50.7, 44.8, 42.3, 37.3, 24.0. [α]26D = -30.1 (c 0.50, CH3OH). HRMS

[M+H]+

calcd.

for

C28H29N4O4:

485.2193;

found:

485.2189.

(2S,3R,5S,9S)-N-(4-

(hydroxycarbamoyl)benzyl)-6-oxo-2,9-diphenyl-1,7-diazaspiro[4.4]nonane-3-carboxamide

(ent-14).

The title compounds was obtained from ent-13 as a pale red solid (594 mg, 1.23 mmol, 98%). [α]26D = +30.7 (c 0.78, CH3OH). 5. Computational Methods DFT

calculations

were

performed

with

the

Gaussian

09

package.10

The

ONIOM(B3LYP/LANL2DZ):PM6 method11-13 was employed for the optimization of the stationary points along the frustrated (3 + 2) cycloadditions between imines and nitrostyrene (2a). B3LYP/631+G* level of theory was used for the optimization of the stationary points along the reaction of azomethine ylides INT3a,e and nitrostyrene (2a). Single-point calculations of the optimized geometries were performed using the M06 functional12f and the 6-31++G(d,p) basis set for the C, N, P, H and O atoms and LANL2DZ effective core potential the for Cu, Ag and Fe atoms. The geometries for all species described were optimized in the gas phase without symmetry restrictions. Frequency calculations were performed on the optimized structures at the same level of theory used to characterize the stationary points (see the Supporting Information for additional details).

ASSOCIATED CONTENT


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Supporting Information. Full characterization of all novel compounds. Cartesian coordinates, harmonic analyses and energies of all the stationary points discussed in this work. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author * [email protected] ACKNOWLEDGMENT Financial support was provided by the Ministerio de Economía y Competitividad (MINECO) of Spain and FEDER (project CTQ2013-45415-P), the UPV/EHU (UFI11/22 QOSYC), and the Basque Government (GV/EJ, grant IT-324-07). The authors thank the SGI/IZO-SGIker UPV/EHU and the DIPC for generous allocation of computational and analytical resources. Coordination of the biological assays on compound 14 by Y. Wang (Reaction Biology Corp. PA, USA) is also gratefully acknowledged. OIDD screening data of compounds 5c and ent-5b,c supplied courtesy of Eli Lilly and Company -used with Lilly's permission. To learn more about the Lilly Open Innovation Drug Discovery platform, please visit the program website at https://openinnovation.lilly.com (last accessed on 21-08-2015). REFERENCES (1) (a) Houk, K. N.; González, J.; Y. Li. Acc. Chem. Res. 1995, 28, 81-90. (b) Rostovsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem. 2002, 114, 2708-2711; Angew. Chem. Int. Ed. 2002, 41, 2596-2599. (c) Reboredo, S.; Reyes, E.; Vicario J. L.; Badía, D.; Carrillo, L.; de Cózar, A.; Cossío F. P. Chem. Eur. J. 2012, 18, 7179-7188. (2) de Cózar, A.; Cossío, F. P. Phys. Chem. Chem. Phys. 2011, 13, 10858-10868.



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(10) Gaussian 09, Revision D.01, Frisch M. J. et al., Gaussian, Inc., Wallingford CT, 2009 (full reference in the Supporting Information). (11) Dapprich, S.; Komuromi, I.; Byun, K. S.; Morokuma, K.; Frisch, M. J. J. Mol. Struct. (Theochem) 1999, 462, 1-21. (12) (a) Vosko, S. H.; Wilk, L.; Nusair, M. Can. J. Phys. 1980, 58, 1200-1211. (b) Lee, C.; Yang, W.; Parr, R. G.; Phys. Rev. B. 1988, 37, 785-789. (c) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652. (d) Stephens, P. J.; Devlin, F. J.; Chabolowski, C. I.; Frisch, M. J. J. Phys. Chem. 1994, 98, 11623-11627. (e) Stewart, J. J. P. J. Mol. Model. 2007, 13, 1173-1213. (f) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215-241. (13) (a) Wadt.; W. R. Hay, P. J. J. Chem. Phys. 1985, 82, 284-298. (b) Hay, P. J. W Wadt,. R. J. Chem. Phys. 1985, 82, 299-310. (14) CCDC 1046812 (cis-6b), 1040895 (5a), and 1040896 (5e) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif . (15) Lee, J. A.; Hu, S.; Willard, F. S.; Cox, K. L.; Galvin, R. J. S.; Peery, R. B.; Oliver, S. H.; Oler, J.; Meredith, T. D.; Heidler, S. A.; Gough, W. H.; Husain, S.; Palkowitz, A. D.; Moxham, C. M. J. Biomol. Screen. 2011, 16, 588-602. (16) Kaeling Jr., W. G. Nat. Rev. Cancer 2005, 5, 689-698. (17) Beck, D. B.; Oda, H.; Shen, S. S.; Reinberg, D. Genes Dev. 2012, 26, 325-337. (18) Chase, A.; Cross, N. C. P. Clin. Cancer Res. 2011, 17, 2613-2618. (19) Dib-Hajj, S. D.; Yang, Y.; Black, J. A.; Waxman, S. G. Nat. Rev. Neurosci. 2013, 14, 49-62. (20) R Vogel,. A. J. Am. Coll. Cardiol. 2012, 59, 2354-2355. 45 ACS Paragon Plus Environment


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R3

R2

R4 O O2N

Y=Z=Ph

Y=PMP Z=H

R1

Z

cat* Y

R4 R1

HN N H

R3

O2N CO2Me N H

Fe

cat*

CO2Me Ph

R3 R2

O

N

PPh 2

R2

R4 R1

HN

cat*: NH-D-EhuPhos

O

N H

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Enantiodivergent Synthesis of Bis ... - ACS Publications

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